78 results on '"Jeremy I. Levin"'
Search Results
2. Late-stage optimization of a tercyclic class of S1P 3 -sparing, S1P 1 receptor agonists
- Author
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Christian Harcken, Morrison B. Mac, Melissa Hill-Drzewi, Debbie Studwell, Diva Sze-Ming Chan, Donna Terenzzio, Heather Xia, Mita Patel, Yu Hui, Brian Linehan, Pingrong Liu, Lynne Canne Bannen, Raymond A. Kemper, Louise K. Modis, Dustin Smith, Lemieux Rene M, Miller Craig Andrew, Darren Disalvo, Raj Betageri, Jeremy I. Levin, Kimberly Fletcher, Daniel Kuzmich, Lori Patenaude, Stephanie M. Ng, Yong Wang, Eugene R. Hickey, Wei Xu, John Lord, Monica Patel, Can Mao, Horan Joshua Courtney, and Tamara Denise Hopkins
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0301 basic medicine ,Molecular charge ,Clinical Biochemistry ,Glutamic Acid ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,Structure-Activity Relationship ,03 medical and health sciences ,Thiadiazoles ,Drug Discovery ,Animals ,Humans ,Potency ,Solubility ,Molecular Biology ,Oxadiazoles ,S1p1 receptor ,Chemistry ,Organic Chemistry ,Late stage ,Brain ,Hydrogen Bonding ,Hep G2 Cells ,Rats ,Kinetics ,Receptors, Lysosphingolipid ,030104 developmental biology ,Molecular Medicine - Abstract
Poor solubility and cationic amphiphilic drug-likeness were liabilities identified for a lead series of S1P3-sparing, S1P1 agonists originally developed from a high-throughput screening campaign. This work describes the subsequent optimization of these leads by balancing potency, selectivity, solubility and overall molecular charge. Focused SAR studies revealed favorable structural modifications that, when combined, produced compounds with overall balanced profiles. The low brain exposure observed in rat suggests that these compounds would be best suited for the potential treatment of peripheral autoimmune disorders.
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- 2016
3. Discovery of a stable macrocyclic o-aminobenzamide Hsp90 inhibitor which significantly decreases tumor volume in a mouse xenograft model
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Zhong Li, Judy Lucas, Jonathan D. Bloom, Russell Dushin, Hao Liu, Mercy Otteng, Mark Johnson, Thomas Nittoli, Jeremy I. Levin, Andrea Olland, Jennifer M. Golas, Christoph W. Zapf, Erik Vogan, Antonia A. Nikitenko, and Frank Boschelli
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Lung Neoplasms ,Macrocyclic Compounds ,Transplantation, Heterologous ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,Administration, Oral ,Mice, Nude ,Pharmaceutical Science ,Heterologous ,Antineoplastic Agents ,Pharmacology ,Biochemistry ,Hsp90 inhibitor ,Mice ,Drug Discovery ,medicine ,Animals ,Humans ,Potency ,HSP90 Heat-Shock Proteins ,Binding site ,Lung cancer ,Molecular Biology ,Binding Sites ,biology ,Chemistry ,Organic Chemistry ,medicine.disease ,Hsp90 ,Protein Structure, Tertiary ,Rats ,Transplantation ,Benzamides ,Microsomes, Liver ,biology.protein ,Microsome ,Molecular Medicine ,Biomarkers - Abstract
An extension of our previously reported series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. Addition of a second methyl group to the tether provided analogs that show increased potency in binding as well as cell-proliferation assays and, more importantly, are stable toward microsomes. We wish to disclose the discovery of a macrocycle which showed impressive biomarker activity 24-h post dosing and which demonstrated prolonged exposure in tumors. When studied in a lung cancer xenograft model, the compound demonstrated significant tumor size reduction.
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- 2011
4. Discovery of a macrocyclic o-aminobenzamide Hsp90 inhibitor with heterocyclic tether that shows extended biomarker activity and in vivo efficacy in a mouse xenograft model
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Judy Lucas, Russell Dushin, Christoph W. Zapf, Jamie L. McBean, Hao Liu, Jennifer M. Golas, Frank Boschelli, Erik Vogan, Jeremy I. Levin, and Jonathan D. Bloom
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Models, Molecular ,Macrocyclic Compounds ,Lactams, Macrocyclic ,Clinical Biochemistry ,hERG ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,Hsp90 inhibitor ,Inhibitory Concentration 50 ,Mice ,In vivo ,Cell Line, Tumor ,Neoplasms ,Drug Discovery ,Benzoquinones ,Biomarkers, Tumor ,Animals ,Humans ,HSP90 Heat-Shock Proteins ,Amines ,Molecular Biology ,Cell Proliferation ,Molecular Structure ,biology ,Drug discovery ,Chemistry ,Organic Chemistry ,Biological activity ,Xenograft Model Antitumor Assays ,In vitro ,Cell culture ,Enzyme inhibitor ,Benzamides ,biology.protein ,Molecular Medicine - Abstract
A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research, heterocycle-containing tethers were explored with the intent to further improve potency and minimize hERG liabilities. This effort culminated in the discovery of compound 10, which efficiently suppressed proliferation of HCT116 and U87 cells. This compound showed prolonged Hsp90-inhibitory activity at least 24h post-administration consistent with elevated and prolonged exposure in the tumor. When studied in a xenograft model, the compound demonstrated significant suppression of tumor growth.
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- 2011
5. Macrocyclic lactams as potent Hsp90 inhibitors with excellent tumor exposure and extended biomarker activity
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Charles Ingalls, Christoph W. Zapf, Hao Liu, Thomas Nittoli, Judy Lucas, Erik Vogan, Jamie L. McBean, Russell Dushin, Mercy Otteng, Jeremy I. Levin, Frank Boschelli, Yongbo Hu, Jennifer M. Golas, and Bloom Jonathan David
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Models, Molecular ,medicine.drug_class ,Lactams, Macrocyclic ,Clinical Biochemistry ,hERG ,Pharmaceutical Science ,Antineoplastic Agents ,Carboxamide ,Pharmacology ,Crystallography, X-Ray ,Biochemistry ,Inhibitory Concentration 50 ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Humans ,ortho-Aminobenzoates ,HSP90 Heat-Shock Proteins ,Molecular Biology ,Cell Proliferation ,Fluorescent Dyes ,chemistry.chemical_classification ,Molecular Structure ,biology ,Chemistry ,Cell growth ,Organic Chemistry ,Biological activity ,Hsp90 ,In vitro ,Enzyme ,Enzyme inhibitor ,Drug Design ,biology.protein ,Molecular Medicine ,Biomarkers - Abstract
A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research in this area, macrocyclic amides and lactams were explored to reduce the risk of hERG liabilities. This effort culminated in the discovery of compound 38, which showed a favorable in vitro profile, and efficiently suppressed proliferation of several relevant cell lines. This compound showed prolonged Hsp90-inhibitory activity at least 24 h post-administration, consistent with elevated and prolonged exposure in the tumor.
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- 2011
6. Design and SAR of macrocyclic Hsp90 inhibitors with increased metabolic stability and potent cell-proliferation activity
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Charles Ingalls, Yongbo Hu, Jeremy I. Levin, Jennifer M. Golas, Clark Eid, Jamie L. McBean, Russell Dushin, Hao Liu, Christoph W. Zapf, Erik Vogan, John P. Sonye, Jonathan D. Bloom, Thomas Nittoli, Alan G. Sutherland, and Frank Boschelli
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Molecular model ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Crystallography, X-Ray ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,Aniline ,Cell Line, Tumor ,Drug Discovery ,Humans ,Structure–activity relationship ,Moiety ,Computer Simulation ,HSP90 Heat-Shock Proteins ,Binding site ,Cytotoxicity ,Molecular Biology ,Cell Proliferation ,chemistry.chemical_classification ,Binding Sites ,biology ,Chemistry ,Organic Chemistry ,Enzyme ,Enzyme inhibitor ,Drug Design ,Benzamides ,biology.protein ,Molecular Medicine ,Protein Binding - Abstract
A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. A basic nitrogen within the tether linking the aniline nitrogen atom to a tetrahydroindolone moiety allowed access to compounds with good physical properties. Important structure-activity relationship information was obtained from this series which led to the discovery of a soluble and stable compound which is potent in an Hsp90 binding and cell-proliferation assay.
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- 2011
7. Indazolylpyrazolopyrimidine as Highly Potent B-Raf Inhibitors with in Vivo Activity
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Karen Collins, Donald Wojciechowicz, Judy Lucas, Nancy Torres, Jeremy I. Levin, Yongbo Hu, Cilien Hanna, Dan M. Berger, Edward J. Salaski, Eileen Frommer, Minu Dutia, Wang Xiaolun, and Dennis Powell
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Models, Molecular ,Proto-Oncogene Proteins B-raf ,Indazoles ,Transplantation, Heterologous ,Mutant ,Antineoplastic Agents ,Pharmacology ,Mice ,Structure-Activity Relationship ,Pyrimidine analogue ,chemistry.chemical_compound ,Pharmacokinetics ,In vivo ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,Chemistry ,Kinase ,Bridged Bicyclo Compounds, Heterocyclic ,humanities ,Pyrimidines ,Biochemistry ,Mutation ,Pyrazoles ,Molecular Medicine ,Drug Screening Assays, Antitumor ,Selectivity ,Lead compound ,Neoplasm Transplantation - Abstract
Novel indazolylpyrazolo[1,5-a]pyrimidine analogues have been prepared and found to be extremely potent type I B-Raf inhibitors. The lead compound shows good selectivity against a panel of 60 kinases, possesses a desirable pharmacokinetic profile, and demonstrates excellent in vivo antitumor efficacy in B-Raf mutant xenograft models.
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- 2010
8. Discovery of highly potent and selective type I B-Raf kinase inhibitors
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Yongbo Hu, Karen Collins, Edward J. Salaski, Nancy Torres, Eileen Frommer, Dennis Powell, Wang Xiaolun, Jeremy I. Levin, Donald Wojciechowicz, and Dan Maarten Berger
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Models, Molecular ,Proto-Oncogene Proteins B-raf ,Molecular model ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Chemical synthesis ,Substrate Specificity ,Structure-Activity Relationship ,Pyrimidine analogue ,Drug Discovery ,Protein Kinase Inhibitors ,Molecular Biology ,chemistry.chemical_classification ,Molecular Structure ,biology ,Kinase ,Organic Chemistry ,In vitro ,Pyrimidines ,Enzyme ,chemistry ,Enzyme inhibitor ,biology.protein ,Pyrazoles ,Molecular Medicine ,Signal transduction - Abstract
A series of pyrazolo[1,5-alpha]pyrimidine analogs has been prepared and found to be potent and selective B-Raf inhibitors. Molecular modeling suggests they bind to the active conformation of the enzyme.
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- 2009
9. Novel pyrazolopyrimidines as highly potent B-Raf inhibitors
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Nancy Torres, Eileen Frommer, Bloom Jonathan David, Karen Collins, Dunnick Alejandro Lee, George Diamantidis, Yongbo Hu, Minu Dutia, Christoph W. Zapf, Zhang Chunchun, Darrin William Hopper, Dan Maarten Berger, Donald Wojciechowicz, Dennis Powell, Martin Di Grandi, and Jeremy I. Levin
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Proto-Oncogene Proteins B-raf ,Pyridines ,Isostere ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Biochemistry ,Chemical synthesis ,chemistry.chemical_compound ,Cell Line, Tumor ,Drug Discovery ,Humans ,Enzyme Inhibitors ,Cytotoxicity ,Molecular Biology ,Cell Proliferation ,chemistry.chemical_classification ,Indazole ,biology ,Bicyclic molecule ,Cell growth ,Organic Chemistry ,Pyrimidines ,Enzyme ,chemistry ,Enzyme inhibitor ,biology.protein ,Pyrazoles ,Molecular Medicine - Abstract
A novel series of pyrazolo[1,5-a]pyrimidines bearing a 3-hydroxyphenyl group at C(3) and substituted tropanes at C(7) have been identified as potent B-Raf inhibitors. Exploration of alternative functional groups as a replacement for the C(3) phenol demonstrated indazole to be an effective isostere. Several compounds possessing substituted indazole residues, such as 4e, 4p, and 4r, potently inhibited cell proliferation at submicromolar concentrations in the A375 and WM266 cell lines, and the latter two compounds also exhibited good therapeutic indices in cells.
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- 2009
10. Synthesis and activity of quinolinylmethyl P1′ α-sulfone piperidine hydroxamate inhibitors of TACE
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Yuhua Zhang, Mark L. Behnke, Frank Lovering, Jeremy I. Levin, Arie Zask, Vincent Sandanayaka, Yi Zhu, Zhang Chunchun, Weixin Xu, and LinHong Sun
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Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,ADAM17 Protein ,Hydroxamic Acids ,Biochemistry ,Chemical synthesis ,Sulfone ,Mice ,chemistry.chemical_compound ,Piperidines ,Drug Discovery ,Animals ,Humans ,Protease Inhibitors ,Sulfones ,Molecular Biology ,chemistry.chemical_classification ,Hydroxamic acid ,biology ,Organic Chemistry ,Biological activity ,ADAM Proteins ,Enzyme ,chemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,Piperidine ,Selectivity - Abstract
A series of alpha-sulfone piperidine hydroxamate TACE inhibitors 11a-n bearing a quinolinyl methyl P1' group was prepared, and their activity was compared to analogous alpha- and beta-sulfone piperidine hydroxamates with a butynyloxy P1' group. The quinolinyl methyl P1' group affords increased inhibitory enzyme activity relative to the corresponding butynyloxy P1' analogs in the alpha-sulfone piperidine hydroxamate series, and greater selectivity than the corresponding butynyloxy P1' analogs in the beta-sulfone piperidine hydroxamate series.
- Published
- 2009
11. Pyranonaphthoquinone Lactones: A New Class of AKT Selective Kinase Inhibitors Alkylate a Regulatory Loop Cysteine
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Cilien Hanna, Clark Eid, Erick Honores, Weiguo Zhang, Leif M. Laakso, Ayako Yamashita, Bernard Dean Johnson, Leonard A. McDonald, Zhong Li, Weidong Ding, Dennis Powell, Jeremy I. Levin, Girija Krishnamurthy, Keiko Tabei, Jaechul Shim, Edward J. Salaski, Shabana Insaf, Lourdes Toral-Barza, Ker Yu, and Tarek S. Mansour
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Alkylation ,Stereochemistry ,Antineoplastic Agents ,Lactones ,Structure-Activity Relationship ,Cell Line, Tumor ,Drug Discovery ,medicine ,Humans ,Structure–activity relationship ,Cysteine ,Protein kinase B ,Cell Proliferation ,Pyrans ,chemistry.chemical_classification ,biology ,Kinase ,Stereoisomerism ,Oncogene Protein v-akt ,Enzyme ,chemistry ,Mechanism of action ,Biochemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,medicine.symptom ,Signal transduction ,Biomarkers ,Naphthoquinones - Abstract
The naturally occurring pyranonaphthoquinone (PNQ) antibiotic lactoquinomycin and related aglycones were found to be selective inhibitors of the serine-threonine kinase AKT. A set of synthetic PNQs were prepared and a minimum active feature set and preliminary SAR were determined. PNQ lactones inhibit the proliferation of human tumor cell lines containing constitutively activated AKT and show expected effects on cellular biomarkers. Biochemical data are presented supporting a proposed bioreductive alkylation mechanism of action.
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- 2009
12. Identification of potent and selective TACE inhibitors via the S1 pocket
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Yuhua Zhang, Jeffrey Scott Condon, Weixin Xu, Diane Joseph-McCarthy, Jeremy I. Levin, Frank Lovering, Linhong Sun, Henry-Georges Lombart, and Weiheng Wang
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Stereochemistry ,education ,Clinical Biochemistry ,Pharmaceutical Science ,ADAM17 Protein ,Matrix metalloproteinase ,Crystallography, X-Ray ,Ligands ,Biochemistry ,chemistry.chemical_compound ,Piperidines ,Drug Discovery ,Hydrolase ,Potency ,Protease Inhibitors ,Sulfones ,Molecular Biology ,chemistry.chemical_classification ,Chemistry ,Organic Chemistry ,Metalloendopeptidases ,humanities ,In vitro ,ADAM Proteins ,Enzyme ,Molecular Medicine ,Piperidine ,Selectivity - Abstract
By focusing on the P1 portion of the piperidine β-sulfone ligands we identified a motif that induces selectivity and resulted in a series of TACE inhibitors that demonstrated excellent in vitro potency against isolated TACE enzyme and excellent selectivity over MMPs 1, 2, 9, 13, and 14.
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- 2007
13. Design and synthesis of butynyloxyphenyl β-sulfone piperidine hydroxamates as TACE inhibitors
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Yi Zhu, Yuhua Zhang, Jeremy I. Levin, LinHong Sun, Mila T. Du, Kaapjoo Park, and Alexis Aplasca
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Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,ADAM17 Protein ,Matrix metalloproteinase ,Biochemistry ,Chemical synthesis ,Sulfone ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Piperidines ,In vivo ,Drug Discovery ,Animals ,Potency ,Structure–activity relationship ,Molecular Biology ,chemistry.chemical_classification ,Hydroxamic acid ,biology ,Organic Chemistry ,General Medicine ,Combinatorial chemistry ,In vitro ,ADAM Proteins ,Enzyme ,chemistry ,Enzyme inhibitor ,Drug Design ,biology.protein ,Molecular Medicine ,Piperidine ,Selectivity - Abstract
A series of butynyloxyphenyl beta-sulfone piperidine hydroxamate TACE inhibitors was designed and synthesized. The resulting structure-activity relationship and MMP selectivity of the series were examined. Of the compounds investigated, 17s has excellent in vitro potency against isolated TACE enzyme, shows good selectivity over MMP-1, -2, -7, -8, -9, -13, and -14, and oral activity in an in vivo mouse model of TNF-alpha production.
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- 2006
14. Acetylenic TACE inhibitors. Part 3: Thiomorpholine sulfonamide hydroxamates
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J.S. Skotnicki, James M. Chen, Jun Xu, Dauphine Barone, L.M. Laakso, J. Schmid, Weixin Xu, G. Jin, Terri Cummons, Jeremy I. Levin, and Mila T. Du
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Lipopolysaccharides ,Propanols ,Stereochemistry ,Morpholines ,Clinical Biochemistry ,Administration, Oral ,Pharmaceutical Science ,Ether ,ADAM17 Protein ,Matrix Metalloproteinase Inhibitors ,Crystallography, X-Ray ,Hydroxamic Acids ,Biochemistry ,Chemical synthesis ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Dogs ,In vivo ,Matrix Metalloproteinase 13 ,Drug Discovery ,Animals ,Humans ,Enzyme Inhibitors ,Molecular Biology ,chemistry.chemical_classification ,Sulfonamides ,Hydroxamic acid ,Molecular Structure ,biology ,Acetylene ,Tumor Necrosis Factor-alpha ,Arthritis ,Organic Chemistry ,Haplorhini ,Rats ,Sulfonamide ,ADAM Proteins ,Disease Models, Animal ,Enzyme ,Thiomorpholine ,chemistry ,Enzyme inhibitor ,Alkynes ,biology.protein ,Molecular Medicine ,Collagen ,Caco-2 Cells - Abstract
A series of thiomorpholine sulfonamide hydroxamate TACE inhibitors, all bearing propargylic ether P1′ groups, was explored. In particular, compound 5h has excellent in vitro potency against isolated TACE enzyme and in cells, oral activity in a model of TNF-α production and a collagen-induced arthritis model, was selected as a clinical candidate for the treatment of RA.
- Published
- 2006
15. Potent, selective, and orally bioavailable matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis
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Wei Li, Qin Wang, Jason Shaoyun Xiang, Jeremy I. Levin, Leif M. Laakso, Xuemei Du, Thomas S. Rush, Jennifer R. Thomason, Manus Ipek, Tam Steve Yik-Kai, Yonghan Hu, Jerauld S. Skotnicki, Jean Schmid, Martin J. DiGrandi, and Jianchang Li
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Models, Molecular ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,Administration, Oral ,Pharmaceutical Science ,Osteoarthritis ,Matrix Metalloproteinase Inhibitors ,Matrix metalloproteinase ,Pharmacology ,Biochemistry ,Substrate Specificity ,Inhibitory Concentration 50 ,Pharmacokinetics ,Oral administration ,Matrix Metalloproteinase 13 ,Drug Discovery ,medicine ,Animals ,Collagenases ,Enzyme Inhibitors ,Molecular Biology ,Benzofurans ,chemistry.chemical_classification ,Molecular Structure ,biology ,Organic Chemistry ,medicine.disease ,Bovine Cartilage ,Rats ,Bioavailability ,Enzyme ,chemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine - Abstract
Modification of alpha-biphenylsulfonamidocarboxylic acids led to potent and selective MMP-13 inhibitors. Compound 16 showed 100% oral bioavailability in rats and demonstrated50% inhibition of bovine cartilage degradation at 10 ng/mL.
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- 2005
16. Synthesis and SAR of highly selective MMP-13 inhibitors
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Xuemei Du, Thomas S. Rush, Tam Steve Yik-Kai, Yonghan Hu, Dianne DeVincentis, Jennifer R. Thomason, Kristina Cunningham, Jason Shaoyun Xiang, Jeremy I. Levin, Jianchang Li, Elisabeth A. Morris, Wei Li, Jerauld S. Skotnicki, and Priya S. Chockalingam
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Stereochemistry ,Clinical Biochemistry ,Carboxylic Acids ,Pharmaceutical Science ,Matrix Metalloproteinase Inhibitors ,Matrix metalloproteinase ,Biochemistry ,Chemical synthesis ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Matrix Metalloproteinase 13 ,Drug Discovery ,Collagenases ,Enzyme Inhibitors ,Molecular Biology ,Amination ,Benzofurans ,Aggrecanase ,chemistry.chemical_classification ,Molecular Structure ,biology ,Organic Chemistry ,In vitro ,Sulfonamide ,Enzyme ,chemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,Selectivity ,Sulfur - Abstract
The structure-based design and synthesis of a series of novel biphenyl sulfonamide carboxylic acids as potent MMP-13 inhibitors with selectivity over MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-14, Aggrecanase 1, and TACE are described.
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- 2005
17. Synthesis and SAR of diazepine and thiazepine TACE and MMP inhibitors
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Arie Zask, Xuemei Du, Jeremy I. Levin, Terri Cummons, Semiramis Ayral-Kaloustian, Jerauld S. Skotnicki, Gloria Jean Macewan, Dauphine Barone, Nancy H. Eudy, Vincent Sandanayaka, Guixian Jin, Jun Xu, and Joshua Kaplan
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Clinical Biochemistry ,Pharmaceutical Science ,ADAM17 Protein ,Matrix Metalloproteinase Inhibitors ,Pharmacology ,Biochemistry ,Chemical synthesis ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,In vivo ,Drug Discovery ,Animals ,Thiazepine ,Molecular Biology ,Mice, Inbred BALB C ,Hydroxamic acid ,Molecular Structure ,biology ,Organic Chemistry ,Metalloendopeptidases ,Biological activity ,Azepines ,In vitro ,ADAM Proteins ,Diazepine ,Models, Chemical ,chemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,Female - Abstract
Potent and selective TACE and MMP inhibitors utilizing the diazepine and thiazepine ring systems were synthesized and evaluated for biological activity in in vitro and in vivo models of TNF-α release. Oral activity in the mouse LPS model of TNF-α release was seen. Efficacy in the mouse collagen induced arthritis model was achieved with diazepine 20.
- Published
- 2005
18. Characterization of (2R, 3S)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N,3-dihydroxybutanamide, a potent and selective inhibitor of TNF-α converting enzyme
- Author
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Yi Zhu, Martin Hegen, Qin Wang, Jeremy I. Levin, Guixian Jin, Jay Gibbons, Xuemei Du, Lih-Ling Lin, James C. Keith, Rebecca Cowling, LinHong Sun, Terri Cummons, Yuhua Zhang, Jun Xu, Barbara J. Sheppard, J.S. Skotnicki, Cheryl Nickerson-Nutter, Weixin Xu, and Vikram R. Rao
- Subjects
Lipopolysaccharides ,medicine.medical_specialty ,Immunology ,Nuclease Protection Assays ,Biological Availability ,ADAM17 Protein ,In Vitro Techniques ,Cell Line ,Arthritis, Rheumatoid ,Mice ,In vivo ,Internal medicine ,Animals ,Humans ,Immunology and Allergy ,Medicine ,Protease Inhibitors ,RNA, Messenger ,IC50 ,Whole blood ,Pharmacology ,Sulfonyl ,chemistry.chemical_classification ,Sulfonamides ,Synovitis ,biology ,Tumor Necrosis Factor-alpha ,business.industry ,Synovial Membrane ,Metalloendopeptidases ,Arthritis, Experimental ,Molecular biology ,In vitro ,Rats ,ADAM Proteins ,Endocrinology ,Enzyme ,chemistry ,Mice, Inbred DBA ,Rats, Inbred Lew ,Enzyme inhibitor ,Metalloproteases ,biology.protein ,Tumor necrosis factor alpha ,Collagen ,business - Abstract
TNF-alpha converting enzyme (TACE) is a validated therapeutic target for the development of oral tumor necrosis factor-alpha (TNF-alpha) inhibitors. Here we report the pre-clinical results and characterization of a selective and potent TACE inhibitor, (2R, 3S)-2-([[4-(2-butynyloxy)phenyl]sulfonyl]amino)-N,3-dihydroxybutanamide (TMI-2), in various in vitro and in vivo assays. TMI-2 is a potent TACE inhibitor in an enzymatic FRET assay (IC50=2 nM). It is more than 250-fold selective over MMP-1, -7, -9, -14, and ADAM-10 in vitro. In cell-based assays and human whole blood, TMI-2 inhibits lipopolysaccharide (LPS)-induced TNF secretion with IC50s1 uM. Importantly, TMI-2 inhibits the spontaneous release of TNF-alpha in human synovium tissue explants of rheumatoid arthritis patients with an IC50 of 0.8 microM. In vivo, TMI-2 potently inhibits LPS-induced TNF-alpha production in mice (ED50=3 mg/kg). In the adjuvant-induced arthritis (AIA) model in rats, treatment with TMI-2 at 30 mg/kg and 100 mg/kg p.o. b.i.d. was highly effective in reducing joint arthritis scores. In a semi-therapeutic collagen-induced arthritis (CIA) model in mice, TMI-2 is highly effective in reducing disease severity scores after oral treatment at 100 mg/kg twice per day. In summary, TMI-2 is a potent and selective TACE inhibitor that inhibits TNF-alpha production and reduces the arthritis scores in pre-clinical models. TMI-2 represents a novel class of TACE inhibitors that may be effective and beneficial in the treatment of rheumatoid arthritis as well as other TNF-mediated inflammatory autoimmune diseases.
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- 2004
19. Benzodiazepine inhibitors of the MMPs and TACE. Part 2
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Gloria Jean Macewan, Semiramis Ayral-Kaloustian, Terri Cummons, James M. Chen, Frances C. Nelson, Jun Xu, Dauphine Barone, Efren Guillermo Delos Santos, Mila T. Du, Jeremy I. Levin, and Guixian Jin
- Subjects
Lipopolysaccharides ,Lipopolysaccharide ,medicine.drug_class ,medicine.medical_treatment ,Clinical Biochemistry ,Pharmaceutical Science ,Inflammation ,ADAM17 Protein ,Matrix Metalloproteinase Inhibitors ,Matrix metalloproteinase ,Pharmacology ,Biochemistry ,Monocytes ,Cell Line ,Benzodiazepines ,Mice ,chemistry.chemical_compound ,Drug Discovery ,medicine ,Animals ,Humans ,Enzyme Inhibitors ,Molecular Biology ,Mice, Inbred BALB C ,Mouth ,Benzodiazepine ,biology ,Tumor Necrosis Factor-alpha ,Monocyte ,Organic Chemistry ,Metalloendopeptidases ,In vitro ,ADAM Proteins ,medicine.anatomical_structure ,Cytokine ,chemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,medicine.symptom - Abstract
A series of benzodiazepine MMP/TACE inhibitors bearing polar moieties has been synthesized in an effort to optimize inhibitory activity against LPS-stimulated TNF production in human monocytes and oral activity in a murine LPS model.
- Published
- 2004
20. Synthesis and evaluation of 4-Anilino-6,7-dialkoxy-3-quinolinecarbonitriles as inhibitors of kinases of the Ras-MAPK signaling cascade
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Karen Collins, Nan Zhang, Robert Mallon, Steven C. Kim, Allan Wissner, Carolyn Discafani, Dennis Powell, Constance Kohler, Jeremy I. Levin, Donald Wojciechowicz, Diane H. Boschelli, Dan Maarten Berger, Minu Dutia, Xuemei Du, Nancy Torres, Larry Feldberg, Biqi Wu, and M. Brawner Floyd
- Subjects
Stereochemistry ,Transplantation, Heterologous ,Clinical Biochemistry ,MAP Kinase Kinase 1 ,Pharmaceutical Science ,Antineoplastic Agents ,Biochemistry ,Chemical synthesis ,Inhibitory Concentration 50 ,Mice ,Structure-Activity Relationship ,Cell Line, Tumor ,Nitriles ,Drug Discovery ,Animals ,Humans ,Structure–activity relationship ,Enzyme Inhibitors ,Protein kinase A ,Molecular Biology ,Mitogen-Activated Protein Kinase Kinases ,biology ,Chemistry ,Kinase ,Organic Chemistry ,Neoplasms, Experimental ,Transplantation ,Treatment Outcome ,Enzyme inhibitor ,Mitogen-activated protein kinase ,Quinolines ,biology.protein ,Molecular Medicine ,Signal transduction ,Cell Division ,Signal Transduction - Abstract
4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)]anilino-6,7-diethoxy-3-quinolinecarbonitrile (3) was identified as a MEK1 kinase inhibitor with exceptional activity against LoVo cells. The structure-activity relationships of the C-4 aniline substituents were explored, and water-solubilizing groups were added at the C-7 position to improve physical properties. Secondary cellular assays revealed that a compound possessing the appropriate aniline substituents inhibited MEK1 as well as MAPK phosphorylation, thereby acting as a dual inhibitor of the Ras-MAPK signaling cascade.
- Published
- 2003
21. RAPID, ONE-POT CONVERSION OF ARYL FLUORIDES INTO PHENOLS WITH 2-BUTYN-1-OL AND POTASSIUMt-BUTOXIDE IN DMSO
- Author
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Mila T. Du and Jeremy I. Levin
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Hydrolysis ,chemistry.chemical_compound ,Chemistry ,Yield (chemistry) ,Aryl ,Potassium ,Organic Chemistry ,Microwave irradiation ,Organic chemistry ,chemistry.chemical_element ,Phenols - Abstract
Aryl fluorides react rapidly with 2-butyn-1-ol and potassium t-butoxide in DMSO under microwave irradiation to give propargylic ethers. These ethers isomerize in situ to the corresponding allenyl ethers, which hydrolyze on work-up to give phenols in good yield.
- Published
- 2002
22. Macrocycles in Drug Discovery
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Jeremy I. Levin
- Subjects
Chemistry ,Drug discovery ,Computational biology - Abstract
This book reviews macrocycles in drug discovery, both those of natural origin and semi-synthetic derivatives of natural products, and those designed and synthesized based on principles of medicinal chemistry. The medicinal chemistry of macrocyclic natural products is interesting in itself, but lessons learned from these compounds, in terms of the relationship between structure and desirable physicochemical properties, are now informing the design of fully synthetic macrocyclic drug candidates against a variety of targets including kinases, ATPases, proteases, GPCRs and others. Furthermore, as more non-classical drug targets, such as protein–protein interactions, are pursued in the pharmaceutical industry, macrocyclic molecules are generating increasing interest as they offer a way to provide drug–protein interactions that cover a larger surface area than traditional small molecules. A variety of macrocycles have become important drugs or have been identified as leads to marketed drugs. This text will discuss these compounds, their pharmacology and synthesis, in the context of their broad chemotype as compounds composed of large rings. Providing a wide reaching review of this important area in a single volume, this book will be of interest to biochemists, pharmaceutical scientists and medicinal chemists working in industry or academia.
- Published
- 2014
23. Heteroaryl and cycloalkyl sulfonamide hydroxamic acid inhibitors of matrix metalloproteinases
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Frances C. Nelson, Pranab K. Chanda, Gu Yansong, Michele A. Sharr, John F. DiJoseph, Jerauld S. Skotnicki, Jeremy I. Levin, Rebecca Cowling, Arie Zask, Chu-Lai Hsiao, Scott Cosmi, Amy Sung, Wade Edris, Loran M. Killar, James M. Wilhelm, and Guixian Jin
- Subjects
Matrix metalloproteinase inhibitor ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Matrix Metalloproteinase Inhibitors ,Matrix metalloproteinase ,Hydroxamic Acids ,Biochemistry ,Chemical synthesis ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,chemistry.chemical_compound ,Matrix Metalloproteinase 13 ,Drug Discovery ,Animals ,Combinatorial Chemistry Techniques ,Humans ,Structure–activity relationship ,Protease Inhibitors ,ortho-Aminobenzoates ,Molecular Biology ,chemistry.chemical_classification ,Sulfonamides ,Hydroxamic acid ,biology ,Organic Chemistry ,Sulfonamide ,Enzyme ,chemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine - Abstract
Heteroaryl and cycloalkyl sulfonamide-hydroxamic acid MMP inhibitors were investigated. Of these, the pyridyl analogue 2 is the most potent and selective inhibitor of MMP-9 and MMP-13 in vitro.
- Published
- 2001
24. Structure-Based Design of a Novel, Potent, and Selective Inhibitor for MMP-13 Utilizing NMR Spectroscopy and Computer-Aided Molecular Design
- Author
-
Frances C. Nelson, Robert Powers, Dominick Mobilio, and Arie Zask, Jeremy I. Levin, Ramaswamy Nilakantan, Franklin J. Moy, and James M. Chen
- Subjects
chemistry.chemical_classification ,Chemistry ,Stereochemistry ,High-throughput screening ,General Chemistry ,Nuclear magnetic resonance spectroscopy ,Matrix metalloproteinase ,Structural difference ,Biochemistry ,Combinatorial chemistry ,Solution structure ,Catalysis ,Colloid and Surface Chemistry ,Enzyme ,Structure based ,Selectivity - Abstract
The high-resolution NMR solution structure of the catalytic fragment of human collagenase-3 (MMP-13) was used as a starting point for structure-based design of selective inhibitors for MMP-13. The major structural difference observed between the MMP structures is the relative size and shape of the S1‘ pocket where this pocket is significantly longer for MMP-13, nearly reaching the surface of the protein. On the basis of the extended nature of the MMP-13 S1‘ pocket an inhibitor potent and selective for MMP-13 was designed from an initial high throughput screening (HTS) lead. CL-82198 was identified as a weak (10 μM) inhibitor against MMP-13 while demonstrating no activity against MMP-1, MMP-9, or the related enzyme TACE. The drug-like properties of CL-82198 made it an ideal candidate for optimization of enzyme potency and selectivity. On the basis of NMR binding studies, it was shown that inhibitor CL-82198 bound within the entire S1‘ pocket of MMP-13 which is the basis of its selectivity against MMP-1, MM...
- Published
- 2000
25. Malonyl α-mercaptoketones and α-mercaptoalcohols, a new class of matrix metalloproteinase inhibitors
- Author
-
David A. Harris, Loran M. Killar, Michele A. Sharr, Xiao-Yi Xiao, David Tien, Lihong Shi, Dinesh V. Patel, David Alan Campbell, Jeremy I. Levin, Jerauld S. Skotnicki, Reza Mortezaei, John F. DiJoseph, Marc Navre, Satoru Ida, Yongwen Wang, Christina Louise Leone, and Khehyong Ngu
- Subjects
Matrix metalloproteinase inhibitor ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Matrix Metalloproteinase Inhibitors ,Matrix metalloproteinase ,Hydroxamic Acids ,Biochemistry ,Chemical synthesis ,Stromelysin 1 ,Structure-Activity Relationship ,Drug Discovery ,Protease Inhibitors ,Sulfhydryl Compounds ,Molecular Biology ,chemistry.chemical_classification ,Binding Sites ,Molecular Structure ,biology ,Chemistry ,Organic Chemistry ,Metalloendopeptidases ,Ketones ,In vitro ,Kinetics ,Zinc ,Enzyme ,Matrix Metalloproteinase 9 ,Enzyme inhibitor ,Alcohols ,Drug Design ,biology.protein ,Thiol ,Molecular Medicine ,Matrix Metalloproteinase 1 - Abstract
A novel series of matrix metalloproteinase (MMP) inhibitors is described. Incorporation of a terminal α-mercaptoketone or α-mercaptoalcohol in the zinc binding domain of a series of inhibitors led to compounds exhibiting low nanomolar activity against collagenase-1 (MMP-1), stromelysin (MMP-3), and gelatinase-B (MMP-9).
- Published
- 1998
26. The asymmetric synthesis and in vitro characterization of succinyl mercaptoalcohol and mercaptoketone inhibitors of matrix metalloproteinases
- Author
-
Dinesh V. Patel, Xiao-Yi Xiao, Lihong Shi, Marc Navre, David Campbell, Jerauld S. Skotnicki, Loran M. Killar, Michele A. Sharr, John F. DiJoseph, and Jeremy I. Levin
- Subjects
Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Matrix Metalloproteinase Inhibitors ,Matrix metalloproteinase ,Biochemistry ,Chemical synthesis ,Stromelysin 1 ,Structure-Activity Relationship ,Drug Discovery ,Protease Inhibitors ,Sulfhydryl Compounds ,Molecular Biology ,chemistry.chemical_classification ,Molecular Structure ,biology ,Chemistry ,Organic Chemistry ,Enantioselective synthesis ,Diastereomer ,Metalloendopeptidases ,Succinates ,Ketones ,In vitro ,Kinetics ,Enzyme ,Matrix Metalloproteinase 9 ,Enzyme inhibitor ,Alcohols ,Drug Design ,biology.protein ,Molecular Medicine ,Indicators and Reagents ,Matrix Metalloproteinase 1 - Abstract
A series of succinyl based mercaptoketones and diastereomeric mercaptoalcohols were prepared and evaluated in vitro as inhibitors of the matrix metalloproteinases collagenase-1 (MMP-1), stromelysin (MMP-3), and gelatinase-B (MMP-9).
- Published
- 1998
27. Inhibition of Matrix Metalloproteinases: Structure Based Design
- Author
-
Arie Zask, Jeremy I. Levin, Loran M. Killar, and Jerauld S. Skotnicki
- Subjects
Pharmacology ,Drug Discovery - Abstract
Matrix metalloproteinases (MMP) have been implicated in a variety of diseases in which the destruction of connective tissue is an important pathological event. These include osteo and rheumatoid arthritis, tumor metastasis and angiogenesis, and corneal ulceration. As a result, there has been a great deal of activity directed towards the design of MMP inhibitors as therapeutic agents for the treatment of these conditions. Progress in the field has now evolved to a degree where potent, low molecular weight, orally active inhibitors have been discovered and advanced to clinical trials. While a majority of inhibitors are dipeptide derivatives, a non-peptide, orally active inhibitor has recently been reported. Some success has also been achieved in the design of subtype selective MMP inhibitors. The elucidation of X-ray and 0NMR structures of several MMPs, and the ability to create homology models of others has provided an understanding of some of the structural requirements leading to potency and specificity. Herein is a review of recent advances in the biology and chemistry of MMPs and MMP inhibitors, including the association of MMPs with specific disease processes, structure activity relationships of MMP inhibitors and factors affecting enzyme specificity and their correlation with MMP structure.
- Published
- 1996
28. The preparation of forskolin analogs via quinone Diels-Alder reactions
- Author
-
Jeremy I. Levin
- Subjects
chemistry.chemical_classification ,chemistry.chemical_compound ,Forskolin ,chemistry ,Organic Chemistry ,Drug Discovery ,Diels alder ,Organic chemistry ,Biochemistry ,Quinone ,Tricyclic - Abstract
A practical synthetic route for the preparation of compound 2a , a carbocyclic analog of the Δ5-derivative, 1 , of forskolin has been completed. A quinone Diels-Alder reaction is used for the rapid construction of the tricyclic framework of 2 .
- Published
- 1996
29. Anti-Inflammatory Drug Discovery
- Author
-
Jeremy I. Levin
- Subjects
MAP kinase kinase kinase ,Sphingosine ,Pharmacology ,Mitogen-activated protein kinase kinase ,Biology ,Tropomyosin receptor kinase C ,chemistry.chemical_compound ,Biochemistry ,Sphingosine kinase 1 ,chemistry ,biology.protein ,ASK1 ,Cyclin-dependent kinase 9 ,Tyrosine kinase - Abstract
Anti-Inflammatory Drug Discovery provides a comprehensive review of recent medicinal chemistry approaches to a variety of important therapeutic targets and provides a key reference for those interested in the prosecution of modern drug discovery programs directed at anti-inflammatory mechanisms of action. The editors, with extensive experience in this field, have selected key thought-leaders who will bring their experience to the medicinal chemistry literature for each target, ranging from components of the arachadonic acid cascade, to kinases, GPCRs, sphingolipids and others, to summarize its background biology and detail new insights, major advances and issues related to bringing new anti-inflammatory therapies to market. Consisting of five main sections key targets covered will include the AA Cascade: mPGES1, cPLA2, Leukotriene A4 Hydrolase, CRTH2; Kinases: P38/PDE4, MAPKAP Kinase 2 (MK2), Syk Kinase Inhibitors, Jak Kinases, IKK , Bruton's Tyrosine Kinase; GPCRs: CCR1, CCR2 Antagonists, CB2 Agonists; Sphingolipids: S1P1 Receptor Agonists, Sphingosine Lyase and Sphingosine Kinase 1 and a final miscellaneous section that looks at Non-Steroidal Dissociated Glucocorticoid Receptor Agonists. The book will be essential reading for pharmacologists, medicinal chemists and pharmaceutical scientists working in industry and academia.
- Published
- 2012
30. ChemInform Abstract: The Asymmetric Synthesis and in vitro Characterization of Succinyl Mercaptoalcohol and Mercaptoketone Inhibitors of Matrix Metalloproteinases
- Author
-
Marc Navre, Lihong Shi, John F. DiJoseph, Jeremy I. Levin, Loran M. Killar, Michele A. Sharr, David Campbell, Jerauld S. Skotnicki, Xiao-Yi Xiao, and Dinesh V. Patel
- Subjects
Chemistry ,Stereochemistry ,Enantioselective synthesis ,Diastereomer ,General Medicine ,Matrix metalloproteinase ,In vitro - Abstract
A series of succinyl based mercaptoketones and diastereomeric mercaptoalcohols were prepared and evaluated in vitro as inhibitors of the matrix metalloproteinases collagenase-1 (MMP-1), stromelysin (MMP-3), and gelatinase-B (MMP-9).
- Published
- 2010
31. ChemInform Abstract: The Synthesis and Biological Activity of a Novel Series of Diazepine MMP Inhibitors
- Author
-
Michele A. Sharr, John F. DiJoseph, Amy Sung, C. E. Roth, Jerauld S. Skotnicki, J. D. Albright, Loran M. Killar, T. Walter, and Jeremy I. Levin
- Subjects
chemistry.chemical_compound ,Diazepine ,MMP Inhibitors ,chemistry ,Biochemistry ,Biological activity ,General Medicine - Published
- 2010
32. ChemInform Abstract: Rapid, One-Pot Conversion of Aryl Fluorides into Phenols with 2-Butyn-1-ol and Potassium t-Butoxide in DMSO
- Author
-
Jeremy I. Levin and Mila T. Du
- Subjects
Substitution reaction ,chemistry.chemical_compound ,Hydrolysis ,chemistry ,Potassium ,Yield (chemistry) ,Aryl ,Microwave irradiation ,Organic chemistry ,chemistry.chemical_element ,General Medicine ,Phenols - Abstract
Aryl fluorides react rapidly with 2-butyn-1-ol and potassium t-butoxide in DMSO under microwave irradiation to give propargylic ethers. These ethers isomerize in situ to the corresponding allenyl ethers, which hydrolyze on work-up to give phenols in good yield.
- Published
- 2010
33. Non-hinge-binding pyrazolo[1,5-a]pyrimidines as potent B-Raf kinase inhibitors
- Author
-
Steven C. Kim, Yongbo Hu, Nancy Torres, Dan Maarten Berger, Ariamala Gopalsamy, Kyung-Hee Kim, Weixin Xu, Donald Wojciechowicz, Larry Feldberg, Jeremy I. Levin, Dennis Powell, James M. Wilhelm, Greg Ciszewski, Eileen Frommer, Karen Collins, Minu Dutia, and Robert Mallon
- Subjects
Models, Molecular ,Proto-Oncogene Proteins B-raf ,medicine.drug_class ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Carboxamide ,Crystallography, X-Ray ,Biochemistry ,Chemical synthesis ,chemistry.chemical_compound ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Transferase ,Structure–activity relationship ,Molecular Biology ,Protein Kinase Inhibitors ,Trifluoromethyl ,Molecular Structure ,Kinase ,Chemistry ,Aryl ,Organic Chemistry ,Stereoisomerism ,Pyrimidines ,Benzamides ,Molecular Medicine ,Pyrazoles - Abstract
As part of our research effort to discover B-Raf kinase inhibitors, we prepared a series of C-3 substituted N-(3-(pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-3-(trifluoromethyl)benzamides. X-ray crystallography studies revealed that one of the more potent inhibitors (10n) bound to B-Raf kinase without forming a hinge-binding hydrogen bond. With basic amine residues appended to C-3 aryl residues, cellular activity and solubility were enhanced over previously described compounds of this class.
- Published
- 2009
34. 3,4-Disubstituted benzofuran P1' MMP-13 inhibitors: optimization of selectivity and reduction of protein binding
- Author
-
Priya S. Chockalingam, Elisabeth A. Morris, Tam Steve Yik-Kai, Dianne DeVincentis, Thomas S. Rush, Yonghan Hu, Rajeev Hotchandani, Jianchang Li, Jeremy I. Levin, Xuemei Du, Jennifer R. Thomason, Junjun Wu, Wei Li, and Jerauld S. Skotnicki
- Subjects
Stereochemistry ,Clinical Biochemistry ,Substituent ,Pharmaceutical Science ,Plasma protein binding ,Matrix Metalloproteinase Inhibitors ,Biochemistry ,chemistry.chemical_compound ,Structure-Activity Relationship ,Drug Discovery ,Pyridine ,Matrix Metalloproteinase 13 ,Moiety ,Animals ,Protease Inhibitors ,Threonine ,Benzofuran ,Molecular Biology ,Serum Albumin ,Benzofurans ,biology ,Chemistry ,Organic Chemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,Matrix Metalloproteinase 2 ,Rabbits ,Selectivity ,Protein Binding - Abstract
Potent 3,4-disubstituted benzofuran P1' MMP-13 inhibitors have been prepared. Selectivity over MMP-2 was achieved through a substituent at the C4 position of the benzofuran P1' moiety of the molecule. By replacing a backbone benzene with a pyridine and valine with threonine, compounds (e.g., 44) with greatly reduced plasma protein binding were also obtained.
- Published
- 2009
35. Synthesis and activity of tryptophan sulfonamide derivatives as novel non-hydroxamate TNF-alpha converting enzyme (TACE) inhibitors
- Author
-
Jeremy I. Levin, John W. Ellingboe, Kaapjoo Park, Ariamala Gopalsamy, Weixin Xu, Alexis Aplasca, and Yuhua Zhang
- Subjects
Models, Molecular ,Stereochemistry ,Clinical Biochemistry ,Carboxylic Acids ,Pharmaceutical Science ,ADAM17 Protein ,Biochemistry ,Chemical synthesis ,Cell Line ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Drug Discovery ,Hydrolase ,Structure–activity relationship ,Animals ,Enzyme Inhibitors ,Molecular Biology ,Indole test ,chemistry.chemical_classification ,Sulfonamides ,biology ,Molecular Structure ,Chemistry ,Organic Chemistry ,Tryptophan ,Sulfonamide ,Enzyme Activation ,ADAM Proteins ,Enzyme ,Enzyme inhibitor ,biology.protein ,Molecular Medicine - Abstract
A novel series of non-hydroxamate tryptophan sulfonamide derivatives containing a butynyloxy P1' moiety was identified as inhibitors of TNF-alpha converting enzyme (TACE). The structure-activity relationship of the series was examined via substitution on the tryptophan indole ring. Of the compounds investigated, 2-(4-(but-2-ynyloxy)phenylsulfonamido)-3-(1-(4-methoxybenzyl)-1H-indol-3-yl)propanoic acid (12p) has the best in vitro potency against isolated TACE enzyme with an IC(50) of 80 nM. Compound 12p also shows good selectivity over MMP-1, -13, -14.
- Published
- 2009
36. Discovery of lactoquinomycin and related pyranonaphthoquinones as potent and allosteric inhibitors of AKT/PKB: mechanistic involvement of AKT catalytic activation loop cysteines
- Author
-
Valerie S. Bernan, Robert T. Abraham, Ker Yu, Edward J. Salaski, Girija Krishnamurthy, Weidong Ding, Judy Lucas, Ping Cai, Jeremy I. Levin, Tarek S. Mansour, Xinyi Huang, Leonard A. McDonald, James Joseph Gibbons, Weiguo Zhang, Laurel R. Barbieri, Yong Bo Hu, and Lourdes Toral-Barza
- Subjects
RNA Caps ,Cancer Research ,Time Factors ,Allosteric regulation ,AKT1 ,Down-Regulation ,Catalysis ,Substrate Specificity ,Structure-Activity Relationship ,Adenosine Triphosphate ,Allosteric Regulation ,Cell Line, Tumor ,medicine ,Staurosporine ,PTEN ,Animals ,Humans ,Cysteine ,Enzyme Inhibitors ,Phosphorylation ,Protein kinase B ,PI3K/AKT/mTOR pathway ,biology ,Kinase ,TOR Serine-Threonine Kinases ,Cell biology ,Rats ,Enzyme Activation ,Kinetics ,Oncology ,Protein Biosynthesis ,biology.protein ,Protein Kinases ,Proto-Oncogene Proteins c-akt ,medicine.drug ,Naphthoquinones - Abstract
The serine/threonine kinase AKT/PKB plays a critical role in cancer and represents a rational target for therapy. Although efforts in targeting AKT pathway have accelerated in recent years, relatively few small molecule inhibitors of AKT have been reported. The development of selective AKT inhibitors is further challenged by the extensive conservation of the ATP-binding sites of the AGC kinase family. In this report, we have conducted a high-throughput screen for inhibitors of activated AKT1. We have identified lactoquinomycin as a potent inhibitor of AKT kinases (AKT1 IC50, 0.149 ± 0.045 μmol/L). Biochemical studies implicated a novel irreversible interaction of the inhibitor and AKT involving a critical cysteine residue(s). To examine the role of conserved cysteines in the activation loop (T-loop), we studied mutant AKT1 harboring C296A, C310A, and C296A/C310A. Whereas the ATP-pocket inhibitor, staurosporine, indiscriminately targeted the wild-type and all three mutant-enzymes, the inhibition by lactoquinomycin was drastically diminished in the single mutants C296A and C310A, and completely abolished in the double mutant C296A/C310A. These data strongly implicate the binding of lactoquinomycin to the T-loop cysteines as critical for abrogation of catalysis, and define an unprecedented mechanism of AKT inhibition by a small molecule. Lactoquinomycin inhibited cellular AKT substrate phosphorylation induced by growth factor, loss of PTEN, and myristoylated AKT. The inhibition was substantially attenuated by coexpression of C296A/C310A. Moreover, lactoquinomycin reduced cellular mammalian target of rapamycin signaling and cap-dependent mRNA translation initiation. Our results highlight T-loop targeting as a new strategy for the generation of selective AKT inhibitors. [Mol Cancer Ther 2007;6(11):OF1–11]
- Published
- 2007
37. Structure-based design of TACE selective inhibitors: manipulations in the S1'-S3' pocket
- Author
-
Junqing Cui, Diane Joseph-McCarthy, Jeremy I. Levin, Adrian Huang, Yuhua Zhang, Yi Zhu, Linhong Sun, Weixin Xu, Weiheng Wang, and Frank Lovering
- Subjects
Models, Molecular ,Matrix metalloproteinase inhibitor ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,ADAM17 Protein ,Matrix Metalloproteinase Inhibitors ,Hydroxamic Acids ,Biochemistry ,Chemical synthesis ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,In vivo ,Drug Discovery ,Hydrolase ,Structure–activity relationship ,Animals ,Enzyme Inhibitors ,Molecular Biology ,chemistry.chemical_classification ,Hydroxamic acid ,biology ,Molecular Structure ,Chemistry ,Tumor Necrosis Factor-alpha ,Organic Chemistry ,Matrix Metalloproteinases ,ADAM Proteins ,Enzyme ,Enzyme inhibitor ,biology.protein ,Molecular Medicine - Abstract
A series of beta-sulfonyl hydroxamate TACE inhibitors, bearing a butynylamino or a butynyloxy P1' group, was designed and synthesized. Of the compounds investigated, 22 has excellent potency against isolated TACE enzyme, shows good selectivity over MMP-2 and MMP-13, and oral activity in an in vivo mouse model of TNF-alpha production.
- Published
- 2007
38. Chapter 18 Recent Progress on Novel HCV Inhibitors
- Author
-
Bloom Jonathan David, Christoph W. Zapf, and Jeremy I. Levin
- Subjects
NS3 ,Proteases ,Protease ,viruses ,medicine.medical_treatment ,Hepatitis C virus ,virus diseases ,biochemical phenomena, metabolism, and nutrition ,Biology ,biology.organism_classification ,medicine.disease_cause ,Virology ,digestive system diseases ,NS2-3 protease ,Flaviviridae ,chemistry.chemical_compound ,Viral replication ,chemistry ,medicine ,NS5B - Abstract
Publisher Summary Hepatitis C virus (HCV) is a blood-borne pathogen belonging to the Flaviviridae family of viruses, which also includes the West Nile, Yellow Fever, and Dengue viruses. Most small molecule inhibitor approaches to HCV have been focused on inhibition of essential viral targets, particularly the NS3-4A protease and the NS5B RNA-dependent RNA polymerase although other targets are being pursued. A variety of nucleoside competitive inhibitors of HCV NS5B, the RdRp encoded at the 3´-terminal portion of the HCV genome and required for viral replication, have also been thoroughly studied and advanced to clinical trials. By analogy to AIDS, where HIV protease plays a crucial role in processing mature virions, HCV uses the NS3-4A (aka NS3) protease in a similar manner making it a very attractive inhibition target. The key difference between the two proteases is that the HIV protease active site forms a well-defined active site while the NS3 protease has a shallow cleft with fewer opportunities to bind to small molecules. As a result, NS3 inhibitors have been generally more complex, more peptide-like and larger than those for HIV.
- Published
- 2007
39. A rat pharmacokinetic/pharmacodynamic model for assessment of lipopolysaccharide-induced tumor necrosis factor-alpha production
- Author
-
Jeremy I. Levin, Qin Wang, Xin Xu, Neal Green, Vikram Patel, Nevena Mollova, Shannon Chesley, John W. Cuozzo, Yuhua Zhang, Uma Raut, Lih-Ling Lin, and J. Perry Hall
- Subjects
Lipopolysaccharides ,Lipopolysaccharide ,Pharmacology ,ADAM17 Protein ,Toxicology ,Models, Biological ,chemistry.chemical_compound ,Pharmacokinetics ,In vivo ,medicine ,Potency ,Animals ,Humans ,Sulfonamides ,business.industry ,Tumor Necrosis Factor-alpha ,Biological activity ,medicine.disease ,Rats ,ADAM Proteins ,chemistry ,Rats, Inbred Lew ,Rheumatoid arthritis ,Pharmacodynamics ,Tumor necrosis factor alpha ,Female ,business - Abstract
Introduction Tumor necrosis factor-alpha (TNFα) participates in many inflammatory processes. TNFα modulators show beneficial effects for the treatment of many diseases including rheumatoid arthritis. The purpose of this study was to validate a rat pharmacokinetic/pharmacodynamic (PK/PD) model for rapid assessment of drug candidates that intended to interrupt TNFα synthesis or release. Methods Rats received intravenous (IV) or oral administrations of test article or dose vehicle, followed by LPS challenge. Plasma levels of test article and TNFα were determined. The areas under the concentration–time curves (AUCdrug and AUCTNFα) were calculated. The overall percentage of inhibition on TNFα release in vivo was calculated by comparing AUCTNFα of the test article treated group against that for the vehicle control group. Results The dosing vehicles tested in this study did not increase plasma TNFα level. At IV dose of up to 100 μg/kg, LPS did not alter the pharmacokinetics of the compound tested. Using a selective TNFα converting enzyme (TACE) inhibitor as model compound, this PK/PD model demonstrated its ability to correlate plasma test article concentration with its biological activity of lowering the LPS-induced TNFα plasma levels in vivo. Discussion A rat PK/PD model for evaluation of the effect of drug candidates on LPS-induced TNFα synthesis and/or release has been investigated. This model provides integrated information on pharmacokinetics and in vivo potency of the test articles.
- Published
- 2006
40. Identification of Potent and Selective MMP-13 Inhibitors
- Author
-
Mary Geck, Zhang-Bao Xu, Rajeev Hotchandani, Jeremy I. Levin, Junjun Wu, Xuemei Du, Thomas S. Rush, J.S. Skotnicki, Elisabeth Collins, and Frank Lovering
- Subjects
Models, Molecular ,Matrix metalloproteinase inhibitor ,Clinical Biochemistry ,Administration, Oral ,Pharmaceutical Science ,Articular cartilage ,Pharmacology ,Matrix metalloproteinase ,Crystallography, X-Ray ,Biochemistry ,Substrate Specificity ,Drug Discovery ,Amino Acids ,Chelating Agents ,media_common ,chemistry.chemical_classification ,biology ,Chemistry ,General Medicine ,Zinc ,Enzyme inhibitor ,Molecular Medicine ,Selectivity ,Drug ,media_common.quotation_subject ,In Vitro Techniques ,Matrix Metalloproteinase Inhibitors ,Sensitivity and Specificity ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Pharmacokinetics ,Matrix Metalloproteinase 13 ,Animals ,Structure–activity relationship ,Protease Inhibitors ,Chelation ,Collagenases ,Molecular Biology ,Benzofurans ,Organic Chemistry ,In vitro ,Protein Structure, Tertiary ,Rats ,Bioavailability ,Cartilage ,Enzyme ,Drug Design ,biology.protein ,Cattle ,Explant culture - Abstract
A potent, selective series of MMP-13 inhibitors has been derived from a weak (3.2 microM) inhibitor that did not bear a zinc chelator. Structure-based drug design strategies were employed to append a Zn-chelating group to one end of the molecule and functionality to enhance selectivity to the other. A compound from this series demonstrated rat oral bioavailability and efficacy in a bovine articular cartilage explant model.
- Published
- 2005
41. Acetylenic TACE inhibitors. Part 2: SAR of six-membered cyclic sulfonamide hydroxamates
- Author
-
Jeremy I. Levin, L.M. Laakso, X. Du, James M. Chen, Jun Xu, J.S. Skotnicki, Vincent Sandanayaka, Yuhua Zhang, A.M. Venkatesan, Weixin Xu, Mila T. Du, and A. Zask
- Subjects
Lipopolysaccharides ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Biological Availability ,ADAM17 Protein ,Cysteine Proteinase Inhibitors ,Crystallography, X-Ray ,Hydroxamic Acids ,Biochemistry ,Monocytes ,Cell Line ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,Mice ,Structure-Activity Relationship ,Dogs ,Species Specificity ,In vivo ,Drug Discovery ,Hydrolase ,Structure–activity relationship ,Potency ,Animals ,Humans ,Molecular Biology ,chemistry.chemical_classification ,Sulfonamides ,Hydroxamic acid ,biology ,Molecular Structure ,Tumor Necrosis Factor-alpha ,Organic Chemistry ,Caspase Inhibitors ,Sulfonamide ,Rats ,ADAM Proteins ,Enzyme ,chemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine - Abstract
The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors bearing a butynyloxy P1' group was explored. In particular, compound 5k has excellent in vitro potency against TACE enzyme and in cells, and oral activity in an in vivo model of TNF-alpha production and a collagen-induced arthritis model.
- Published
- 2005
42. Practical Sulfonylation of Amines with 4-Hydroxybenzenesulfonyl Chlorides: In situ Silylation—Desilylation
- Author
-
Kaapjoo Park, Mila T. Du, and Jeremy I. Levin
- Subjects
In situ ,chemistry.chemical_compound ,Trimethylsilyl ,Silylation ,Chemistry ,Organic Chemistry ,medicine ,Phenol ,Organic chemistry ,General Medicine ,Chloride ,Acetamide ,medicine.drug - Abstract
A one‐pot procedure for the efficient sulfonylation of amines with 4‐hydroxybenzenesulfonyl chloride involving in situ protection and deprotection of the phenol with N,O‐bis(trimethylsilyl)acetamide (BTSA) is presented.
- Published
- 2004
43. Benzodiazepine Inhibitors of the MMPs and TACE. Part 2
- Author
-
Jeremy I. Levin and et al. et al.
- Subjects
Benzodiazepine ,Chemistry ,medicine.drug_class ,medicine ,General Medicine ,Matrix metalloproteinase ,Pharmacology - Published
- 2004
44. Sulfonate ester hydroxamic acids as potent and selective inhibitors of TACE enzyme
- Author
-
Jeremy I, Levin and Mila T, Du
- Subjects
Lipopolysaccharides ,Tumor Necrosis Factor-alpha ,Metalloendopeptidases ,ADAM17 Protein ,Matrix Metalloproteinase Inhibitors ,Hydroxamic Acids ,Monocytes ,Substrate Specificity ,ADAM Proteins ,Structure-Activity Relationship ,Matrix Metalloproteinase 13 ,Humans ,Indicators and Reagents ,Protease Inhibitors ,Enzyme Inhibitors ,Cells, Cultured ,Protein Binding - Abstract
Sulfonamide hydroxamate derivatives of anthranilic acids are known to be potent inhibitors of cell-free TACE enzyme. However, compounds of this structural class with both high potency and high selectivity for TACE over matrix metalloproteinases (MMPs) are uncommon. Replacement of the sulfonamide functionality with an isosteric sulfonate ester has resulted in a series of sulfonate ester hydroxamates, 2a-e, with excellent activity against TACE and excellent selectivity over MMP-1 and MMP-13. Although compounds 2a-e possess good permeability in a PAMPA assay, they are only weakly active as inhibitors of lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) production in human monocytic THP-1 cells. Protein binding affinity also does not predict the lack of cellular activity for these analogs.
- Published
- 2004
45. The design and synthesis of aryl hydroxamic acid inhibitors of MMPs and TACE
- Author
-
Jeremy I. Levin
- Subjects
Stereochemistry ,Matrix metalloproteinase inhibitor ,Osteoarthritis ,Matrix metalloproteinase ,Pharmacology ,ADAM17 Protein ,Matrix Metalloproteinase Inhibitors ,Hydroxamic Acids ,chemistry.chemical_compound ,Drug Discovery ,medicine ,Animals ,Humans ,Protease Inhibitors ,chemistry.chemical_classification ,Metalloproteinase ,Hydroxamic acid ,Aryl ,Metalloendopeptidases ,Biological activity ,General Medicine ,medicine.disease ,ADAM Proteins ,Enzyme ,chemistry ,Rheumatoid arthritis ,Drug Design - Abstract
Three different classes of aryl hydroxamic acid scaffolds have been explored and provided potent inhibitors of MMP-1, -2, -9, -13 and TACE. Structure-based design has allowed the evolution of these inhibitors from broad spectrum inhibitors into compounds that are more selective for MMPs relevant to particular disease states. Aryl hydroxamates selective for MMP-9, MMP-13 and TACE have been disclosed that may aid in the study of the physiological role of these enzymes. Furthermore, the different selectivity profiles offered by these MMP/TACE inhibitors may allow the determination of which metalloprotease, or group of metalloproteases, must be inhibited for the safe, long-term treatment of osteoarthritis, rheumatoid arthritis and cancer. Some of these compounds have demonstrated useful biological activity in efficacy models relevant to osteoarthritis and rheumatoid arthritis and are therefore potential clinical candidates.
- Published
- 2004
46. Oxazole Diels—Alder Reactions
- Author
-
Jeremy I. Levin and Leif M. Laakso
- Subjects
General Medicine - Published
- 2004
47. Design strategies for the identification of MMP-13 and Tace inhibitors
- Author
-
Jerauld S, Skotnicki, Martin J, DiGrandi, and Jeremy I, Levin
- Subjects
Metalloendopeptidases ,ADAM17 Protein ,Matrix Metalloproteinase Inhibitors ,Hydroxamic Acids ,Arthritis, Rheumatoid ,ADAM Proteins ,Structure-Activity Relationship ,Zinc ,Drug Design ,Matrix Metalloproteinase 13 ,Osteoarthritis ,Animals ,Humans ,Protease Inhibitors ,Chelating Agents - Abstract
Inhibitors of matrix metalloprotease (MMP)-13 and tumor necrosis factor-alpha converting enzyme (TACE) have been highly sought as potential therapeutic agents for the treatment of osteoarthritis and rheumatoid arthritis, respectively. This review focuses on the published literature on these inhibitors from 2001 to mid-2003. Significant advances have been reported in the design and synthesis of potent and selective inhibitors of MMP-13 using hydroxamic acid and non-hydroxamate zinc chelators on a variety of scaffolds. TACE inhibitors based on variations of known MMP inhibitors scaffolds and novel designs have been reported. Selectivity profiles for these inhibitors range from broad-spectrum to TACE-specific. Future clinical studies on these and other inhibitors will determine which MMP, or set of MMPs, must be inhibited for efficacy and long-term safety.
- Published
- 2003
48. Oxazole Diels–Alder Reactions
- Author
-
Leif M. Laakso and Jeremy I. Levin
- Subjects
chemistry.chemical_compound ,Isoindoles ,chemistry ,Singlet oxygen ,Diels alder ,Organic chemistry ,Eupolauramine ,Gnididione ,Aryne ,Stemoamide ,Oxazole - Published
- 2003
49. Acetylenic TACE inhibitors. Part 1. SAR of the acyclic sulfonamide hydroxamates
- Author
-
Gloria Jean Macewan, Chuansheng Niu, J.S. Skotnicki, Dauphine Barone, A. Zask, C. Crago, Ayral-Kaloustian Semiranis, Amy Sung, Roy A. Black, R. Cowling, Kendall M. Mohler, Terri Cummons, Gulnaz Khafizova, Jeremy I. Levin, Derek C. Cole, E. Delos Santos, E.J. Salaski, Katherine Cheung, G. Jin, Yuhua Zhang, Weixin Xu, X. Du, James M. Chen, and Jun Xu
- Subjects
Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,ADAM17 Protein ,Crystallography, X-Ray ,Hydroxamic Acids ,Biochemistry ,Chemical synthesis ,chemistry.chemical_compound ,Structure-Activity Relationship ,In vivo ,Drug Discovery ,Structure–activity relationship ,ortho-Aminobenzoates ,Enzyme Inhibitors ,Molecular Biology ,chemistry.chemical_classification ,Sulfonamides ,Hydroxamic acid ,biology ,Molecular Structure ,Chemistry ,Acetylene ,Organic Chemistry ,Metalloendopeptidases ,In vitro ,Sulfonamide ,ADAM Proteins ,Enzyme ,Enzyme inhibitor ,biology.protein ,Molecular Medicine - Abstract
The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors, all bearing a butynyloxy P1' group, was explored. In particular, compound 5j has excellent in vitro potency against isolated TACE enzyme and in cells, good selectivity over MMP-1 and MMP-9, and oral activity in an in vivo model of TNF-alpha production and a collagen-induced arthritis model.
- Published
- 2003
50. Synthesis and SAR of bicyclic heteroaryl hydroxamic acid MMP and TACE inhibitors
- Author
-
Loran M. Killar, S. Skala, James M. Chen, X. Du, G. Jin, Roy A. Black, A. Zask, Michele A. Sharr, Gu Yansong, R. Cowling, C.J March, J.S. Skotnicki, J. D. Albright, Amy Sung, Dauphine Barone, John F. DiJoseph, C. E. Roth, Kendall M. Mohler, Jeremy I. Levin, and M. Hogan
- Subjects
Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Biological Availability ,Matrix metalloproteinase ,ADAM17 Protein ,Matrix Metalloproteinase Inhibitors ,Hydroxamic Acids ,Biochemistry ,Chemical synthesis ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,In vivo ,Drug Discovery ,Pyrazolopyridine ,Animals ,Enzyme Inhibitors ,Molecular Biology ,chemistry.chemical_classification ,Hydroxamic acid ,biology ,Bicyclic molecule ,Arthritis ,Organic Chemistry ,Metalloendopeptidases ,Bridged Bicyclo Compounds, Heterocyclic ,Sulfonamide ,Rats ,ADAM Proteins ,Disease Models, Animal ,Cartilage ,chemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,Cattle - Abstract
Potent and selective bicyclic heteroaryl hydroxamic acid MMP and TACE inhibitors were synthesized by a novel convergent route. Selectivity and efficacy versus MMPs and TACE could be controlled by appropriate substitution on the scaffolds and by variation of the P1' group. Select compounds were found to be effective in in vivo models of arthritis.
- Published
- 2003
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