8 results on '"Deanna Mohn"'
Search Results
2. Synthesis and SAR study of potent and selective PI3Kδ inhibitors
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Jamie Wong, Thuy B. Tran, Mario G. Cardozo, Kirk Henne, Tisha San Miguel, Julia Suchomel, Deanna Mohn, Julio C. Medina, Leeanne Zalameda, Daniela Metz, Lawrence R. McGee, Xiao He, Youngsook Shin, Simon Wong, Sharon Wannberg, John D. McCarter, Minna Bui, Xiaolin Hao, and Timothy D. Cushing more...
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Male ,Gene isoform ,Class I Phosphatidylinositol 3-Kinases ,Stereochemistry ,Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Rats ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,Drug Discovery ,Quinolines ,Animals ,Humans ,Protein Isoforms ,Molecular Medicine ,Selectivity ,Protein Kinase Inhibitors ,Molecular Biology - Abstract
2,3,4-Substituted quinolines such as (10a) were found to be potent inhibitors of PI3Kδ in both biochemical and cellular assays with good selectivity over three other class I PI3K isoforms. Some of those analogs showed favorable pharmacokinetic properties. more...
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- 2015
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Catalog
3. Discovery and in Vivo Evaluation of (S)-N-(1-(7-Fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and Related PI3Kδ Inhibitors for Inflammation and Autoimmune Disease
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Andrew Tasker, Andreas Reichelt, Yi-Ling Hu, Deanna Mohn, John McCarter, Ben Fisher, Robert M. Rzasa, Yi Chen, Julio C. Medina, Gang Yu, Sharon Wannberg, Brian Lucas, Ron C. Kelly, Jennifer Seganish, Felix Gonzalez-Lopez de Turiso, Xiaolin Hao, Kristin L. Andrews, Douglas A. Whittington, Matthew Frank Brown, Dawei Zhang, Youngsook Shin, Mario G. Cardozo, Jason Duquette, Robert C. Wahl, Leeanne Zalameda, Daniela Metz, Vatee Pattaropong, Michael G. Johnson, Tisha San Miguel, Randall W. Hungate, John Whoriskey, Lawrence R. McGee, Timothy D. Cushing, Kirk Henne, Liping H. Pettus, and Xiao He more...
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Models, Molecular ,Adenosine ,Class I Phosphatidylinositol 3-Kinases ,Stereochemistry ,Mice, Transgenic ,Pharmacology ,Crystallography, X-Ray ,Autoimmune Diseases ,Structure-Activity Relationship ,In vivo ,Drug Discovery ,Sf9 Cells ,medicine ,Animals ,Humans ,Structure–activity relationship ,Protein Kinase Inhibitors ,IC50 ,Cells, Cultured ,Whole blood ,Inflammation ,Autoimmune disease ,Mice, Inbred BALB C ,Molecular Structure ,Drug discovery ,Kinase ,Chemistry ,medicine.disease ,Protein Structure, Tertiary ,Disease Models, Animal ,Models, Chemical ,Rats, Inbred Lew ,Quinolines ,Molecular Medicine ,Female ,Amine gas treating ,Protein Binding - Abstract
The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation. more...
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- 2014
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4. Discovery and in Vivo Evaluation of Dual PI3Kβ/δ Inhibitors
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Julia Winslow Lohman, David Fong, Michael G. Johnson, Xiaolin Hao, Gang Yu, Douglas A. Whittington, Helen J. McBride, Yi-Ling Hu, Vatee Pattaropong, Lawrence R. McGee, Sharon Wannberg, Kirk Henne, Jillian L. Simard, Xiao He, Deanna Mohn, Julio C. Medina, Kent Miner, Todd J. Kohn, Yi Chen, Felix Gonzalez-Lopez de Turiso, Jennifer Seganish, Mario G. Cardozo, Matthew Frank Brown, Daniela Metz, Youngsook Shin, and Timothy D. Cushing more...
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Models, Molecular ,biology ,Chemistry ,Drug Evaluation, Preclinical ,Rational design ,Arthritis ,Inflammation ,Pharmacology ,medicine.disease ,In vivo ,Rheumatoid arthritis ,Drug Discovery ,medicine ,biology.protein ,Molecular Medicine ,Animal studies ,medicine.symptom ,Protein Kinase Inhibitors ,PI3K/AKT/mTOR pathway ,Keyhole limpet hemocyanin ,Phosphoinositide-3 Kinase Inhibitors - Abstract
Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue 63 was a potent and selective PI3Kβ/δ dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue 63 was found to be efficacious in animal models of inflammation including a keyhole limpet hemocyanin (KLH) study and a collagen-induced arthritis (CIA) disease model of rheumatoid arthritis. These studies highlight the potential therapeutic value of inhibiting both the PI3Kβ and δ isoforms in the treatment of a number of inflammatory diseases. more...
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- 2012
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5. Structure-Guided Design of Aminopyrimidine Amides as Potent, Selective Inhibitors of Lymphocyte Specific Kinase: Synthesis, Structure–Activity Relationships, and Inhibition of in Vivo T Cell Activation
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Kurt Morgenstern, Matthew W. Martin, Faye Hsieh, Stuart C. Chaffee, Susan A. Tomlinson, Susan M. Turci, Joseph J. Nunes, Lilly Chai, Paul E. Rose, Josie H. Lee, Antonio J. Oliveira-dos-Santos, Erin F. DiMauro, Vinod F. Patel, David Powers, Yan Gu, Xin Huang, Jean Bemis, Andrew A. Welcher, David C. Mcgowan, Huilin Zhao, Joseph L. Kim, Xiaotian Zhu, Holly L. Deak, Li Zhu, Yanyan Tudor, Ted Faust, Linda F. Epstein, Christina Boucher, Anu Gore, Deanna Mohn, Stephen Schneider, John Newcomb, Daniela Metz, Brad Henkle, and Paul Gallant more...
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Lipopolysaccharides ,Male ,Models, Molecular ,T-Lymphocytes ,T cell ,Lymphocyte ,Administration, Oral ,Crystallography, X-Ray ,Rats, Sprague-Dawley ,Mice ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Animals ,Humans ,Structure–activity relationship ,Protein Kinase Inhibitors ,Cell Proliferation ,Mice, Knockout ,Mice, Inbred BALB C ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Kinase ,Chemistry ,CD28 ,Stereoisomerism ,Amides ,Rats ,Enzyme Activation ,Killer Cells, Natural ,Pyrimidines ,medicine.anatomical_structure ,Biochemistry ,Lymphocyte Specific Protein Tyrosine Kinase p56(lck) ,Enzyme inhibitor ,Drug Design ,biology.protein ,Interleukin-2 ,Molecular Medicine ,Female ,Signal transduction ,Tyrosine kinase ,Signal Transduction - Abstract
The lymphocyte-specific kinase (Lck), a member of the Src family of cytoplasmic tyrosine kinases, is expressed in T cells and natural killer (NK) cells. Genetic evidence, including knockout mice and human mutations, demonstrates that Lck kinase activity is critical for normal T cell development, activation, and signaling. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disease. With the aid of X-ray structure-based analysis, aminopyrimidine amides 2 and 3 were designed from aminoquinazolines 1, which had previously been demonstrated to exhibit potent inhibition of Lck and T cell proliferation. In this report, we describe the synthesis and structure-activity relationships of a series of novel aminopyrimidine amides 3 possessing improved cellular potency and selectivity profiles relative to their aminoquinazoline predecessors 1. Orally bioavailable compound 13b inhibited the anti-CD3-induced production of interleukin-2 (IL-2) in mice in a dose-dependent manner (ED 50 = 9.4 mg/kg). more...
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- 2008
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6. Discovery, Optimization, and in Vivo Evaluation of Benzimidazole Derivatives AM-8508 and AM-9635 as Potent and Selective PI3Kδ Inhibitors
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Yi-Ling Hu, Leeanne Zalameda, Daniela Metz, Julia Suchomel, Thuy B. Tran, Gang Yu, Jason Duquette, John McCarter, Xuxia Zhang, Youngsook Shin, Simon Wong, Julio C. Medina, Sharon Wannberg, Timothy D. Cushing, Tisha San Miguel, Mario G. Cardozo, Lawrence R. McGee, Ron C. Kelly, Christine Vissinga, Deanna Mohn, John Whoriskey, Douglas A. Whittington, Kirk Henne, and Xiao He more...
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0301 basic medicine ,Models, Molecular ,Benzimidazole ,B-cell receptor ,chemical and pharmacologic phenomena ,Crystallography, X-Ray ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,Pharmacokinetics ,In vivo ,Drug Discovery ,Structure–activity relationship ,Animals ,Humans ,Protein Kinase Inhibitors ,Phosphoinositide-3 Kinase Inhibitors ,B-Lymphocytes ,biology ,Chemistry ,In vitro ,Bioavailability ,Rats ,030104 developmental biology ,Biochemistry ,Immunoglobulin M ,Immunoglobulin G ,Hemocyanins ,biology.protein ,Molecular Medicine ,Benzimidazoles ,Keyhole limpet hemocyanin - Abstract
Lead optimization efforts resulted in the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 1 (AM-8508) and 2 (AM-9635), with good pharmacokinetic properties. The compounds inhibit B cell receptor (BCR)-mediated AKT phosphorylation (pAKT) in PI3Kδ-dependent in vitro cell based assays. These compounds which share a benzimidazole bicycle are effective when administered in vivo at unbound concentrations consistent with their in vitro cell potency as a consequence of improved unbound drug concentration with lower unbound clearance. Furthermore, the compounds demonstrated efficacy in a Keyhole Limpet Hemocyanin (KLH) study in rats, where the blockade of PI3Kδ activity by inbibitors 1 and 2 led to effective inhibition of antigen-specific IgG and IgM formation after immunization with KLH. more...
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- 2015
7. Discovery of Aminoquinazolines as Potent, Orally Bioavailable Inhibitors of Lck: Synthesis, SAR, and in Vivo Anti-Inflammatory Activity
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Joseph L. Kim, Xiaotian Zhu, William H. Buckner, Josie H. Lee, Vinod F. Patel, Lilly Chai, Antonio J. Oliveira-dos-Santos, Ryan White, Holly L. Deak, Brian L. Hodous, Joseph J. Nunes, John L. Buchanan, Paul E. Rose, Huilin Zhao, Andrew A. Welcher, Stephanie D. Geuns-Meyer, Linda F. Epstein, David Powers, Yan Gu, Stephen Schneider, Kurt Morgenstern, Anu Gore, Victor J. Cee, Yanyan Tudor, Ted Faust, Susan A. Tomlinson, Xin Huang, Erin F. DiMauro, Jean Bemis, Susan M. Turci, John Newcomb, David C. Mcgowan, Faye Hsieh, Brad Henkle, Deanna Mohn, Christina Boucher, Li Zhu, Matthew W. Martin, Paul Gallant, Craig E. Masse, and Daniela Metz more...
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Male ,Models, Molecular ,T-Lymphocytes ,T cell ,Administration, Oral ,Biological Availability ,In Vitro Techniques ,Pharmacology ,Rats, Sprague-Dawley ,Mice ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Animals ,Humans ,Structure–activity relationship ,Cells, Cultured ,Cell Proliferation ,Mice, Inbred BALB C ,Tyrosine-protein kinase CSK ,Tumor Necrosis Factor-alpha ,Kinase ,Chemistry ,ZAP70 ,Anti-Inflammatory Agents, Non-Steroidal ,T-cell receptor ,CD28 ,Rats ,medicine.anatomical_structure ,Biochemistry ,Lymphocyte Specific Protein Tyrosine Kinase p56(lck) ,Benzamides ,Quinazolines ,Interleukin-2 ,Molecular Medicine ,Female ,Signal transduction - Abstract
The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and natural killer (NK) cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disease. Screening of our kinase-preferred collection identified aminoquinazoline 1 as a potent, nonselective inhibitor of Lck and T cell proliferation. In this report, we describe the synthesis and structure-activity relationships of a series of novel aminoquinazolines possessing in vitro mechanism-based potency. Optimized, orally bioavailable compounds 32 and 47 exhibit anti-inflammatory activity (ED(50) of 22 and 11 mg/kg, respectively) in the anti-CD3-induced production of interleukin-2 (IL-2) in mice. more...
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- 2006
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8. Novel 2-aminopyrimidine carbamates as potent and orally active inhibitors of Lck: synthesis, SAR, and in vivo antiinflammatory activity
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Debra Zack, David C. Mcgowan, Xiaotian Zhu, Linda F. Epstein, Antonio J. Oliveira-dos-Santos, Ryan White, Christina Boucher, Stephen Schneider, David Powers, Faye Hsieh, Josie H. Lee, Patricia Amouzegh, Huilin Zhao, Spencer Napier, Monika Ermann, Scot Middleton, Daniel Elbaum, Joseph J. Nunes, Xin Huang, Matthew W. Martin, Yanyan Tudor, Paul Gallant, Li Zhu, David N. Johnston, Yan Gu, Kurt Morgenstern, Susan M. Turci, Eoin Christopher Power, Paul E. Rose, Michael Morrison, Theodore Faust, Perry M. Novak, William H. Buckner, Lilly Chai, Jenkins James Edward, Shaun Flynn, John L. Buchanan, Deanna Mohn, Stephanie Sell, Andrew A. Welcher, Daniela Metz, Anu Gore, Chiara Ghiron, John Newcomb, and Armistead David M more...
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Models, Molecular ,T cell ,T-Lymphocytes ,Anti-Inflammatory Agents ,Administration, Oral ,Aminopyridines ,Biological Availability ,In Vitro Techniques ,Crystallography, X-Ray ,Lymphocyte Activation ,Jurkat cells ,Rats, Sprague-Dawley ,Jurkat Cells ,Mice ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Animals ,Humans ,Mice, Inbred BALB C ,biology ,Molecular Structure ,Chemistry ,Kinase ,ZAP70 ,T-cell receptor ,CD28 ,Rats ,medicine.anatomical_structure ,Pyrimidines ,Biochemistry ,Enzyme inhibitor ,Lymphocyte Specific Protein Tyrosine Kinase p56(lck) ,biology.protein ,Molecular Medicine ,Carbamates ,Signal transduction ,Lymphocyte Culture Test, Mixed - Abstract
The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and NK cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the synthesis, structure-activity relationships, and pharmacological characterization of 2-aminopyrimidine carbamates, a new class of compounds with potent and selective inhibition of Lck. The most promising compound of this series, 2,6-dimethylphenyl 2-((3,5-bis(methyloxy)-4-((3-(4-methyl-1-piperazinyl)propyl)oxy)phenyl)amino)-4-pyrimidinyl(2,4-bis(methyloxy)phenyl)carbamate (43) exhibits good activity when evaluated in in vitro assays and in an in vivo model of T cell activation. more...
- Published
- 2006
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