11 results on '"Vaddi K"'
Search Results
2. Potent, exceptionally selective, orally bioavailable inhibitors of TNF-alpha Converting Enzyme (TACE): novel 2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamide P1' substituents.
- Author
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Ott GR, Asakawa N, Lu Z, Anand R, Liu RQ, Covington MB, Vaddi K, Qian M, Newton RC, Christ DD, Trzaskos JM, and Duan JJ
- Subjects
- ADAM17 Protein, Animals, Area Under Curve, Benzamides blood, Benzamides pharmacokinetics, Biological Availability, Dogs, Half-Life, Molecular Structure, Rats, Structure-Activity Relationship, ADAM Proteins antagonists & inhibitors, Benzamides chemistry, Benzamides pharmacology
- Abstract
Novel ((2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamides were found to be excellent P1' substituents in conjunction with unique constrained beta-amino hydroxamic acid scaffolds for the discovery of potent selective inhibitors of TNF-alpha Converting Enzyme (TACE). Optimized examples proved potent for TACE, exceptionally selective over a wide panel of MMP and ADAM proteases, potent in the suppression of LPS-induced TNF-alpha in human whole blood and orally bioavailable.
- Published
- 2008
- Full Text
- View/download PDF
3. Alpha,Beta-cyclic-beta-benzamido hydroxamic acids: Novel oxaspiro[4.4]nonane templates for the discovery of potent, selective, orally bioavailable inhibitors of tumor necrosis factor-alpha converting enzyme (TACE).
- Author
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Ott GR, Asakawa N, Liu RQ, Covington MB, Qian M, Vaddi K, Newton RC, Trzaskos JM, Christ DD, Galya L, Scholz T, Marshall W, and Duan JJ
- Subjects
- ADAM17 Protein, Administration, Oral, Alkanes chemical synthesis, Alkanes pharmacokinetics, Alkanes pharmacology, Animals, Biological Availability, Caco-2 Cells, Humans, Hydroxamic Acids chemical synthesis, Hydroxamic Acids pharmacokinetics, Matrix Metalloproteinase Inhibitors, Matrix Metalloproteinases metabolism, Models, Molecular, Protease Inhibitors chemical synthesis, Protease Inhibitors pharmacokinetics, Rats, Rats, Sprague-Dawley, Spiro Compounds chemical synthesis, Spiro Compounds pharmacokinetics, Spiro Compounds pharmacology, ADAM Proteins antagonists & inhibitors, Alkanes chemistry, Hydroxamic Acids chemistry, Hydroxamic Acids pharmacology, Protease Inhibitors chemistry, Protease Inhibitors pharmacology, Spiro Compounds chemistry
- Abstract
Two novel oxaspiro[4.4]nonane beta-benzamido hydroxamic scaffolds have been synthesized in enantio- and diasteriomerically pure form. These templates proved to be exceptional platforms that have led to the discovery of potent inhibitors of TACE that are active in a cellular assay measuring suppression of LPS-induced TNF-alpha. Furthermore, these inhibitors are selective against related MMPs, demonstrate permeability in a Caco-2 assay, and display good oral bioavailability.
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- 2008
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- View/download PDF
4. Alpha,beta-cyclic-beta-benzamido hydroxamic acids: novel templates for the design, synthesis, and evaluation of selective inhibitors of TNF-alpha converting enzyme (TACE).
- Author
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Ott GR, Asakawa N, Lu Z, Liu RQ, Covington MB, Vaddi K, Qian M, Newton RC, Christ DD, Traskos JM, Decicco CP, and Duan JJ
- Subjects
- ADAM17 Protein, Administration, Oral, Animals, Biological Availability, Chromatography, High Pressure Liquid, Enzyme Inhibitors chemical synthesis, Humans, Hydroxamic Acids administration & dosage, Hydroxamic Acids chemical synthesis, Hydroxamic Acids pharmacokinetics, Rats, Stereoisomerism, ADAM Proteins antagonists & inhibitors, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Hydroxamic Acids chemistry, Hydroxamic Acids pharmacology
- Abstract
Selective inhibitors of TNF-alpha Converting Enzyme (TACE) based on (1R,2S)-cyclopentyl, (3S,4S)-pyrrolidinyl, and (3R,4S)-tetrahydrofuranyl beta-benzamido hydroxamic acids have been synthesized and evaluated. This study has led to the discovery of novel inhibitors whose profiles include activity against TACE in an enzyme assay, potency in the suppression of LPS-stimulated TNF-alpha in human whole blood, selectivity against a panel of MMPs and oral bioavailability.
- Published
- 2008
- Full Text
- View/download PDF
5. Discovery of beta-benzamido hydroxamic acids as potent, selective, and orally bioavailable TACE inhibitors.
- Author
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Duan JJ, Chen L, Lu Z, Xue CB, Liu RQ, Covington MB, Qian M, Wasserman ZR, Vaddi K, Christ DD, Trzaskos JM, Newton RC, and Decicco CP
- Subjects
- ADAM Proteins chemistry, ADAM Proteins metabolism, ADAM17 Protein, Administration, Oral, Animals, Benzamides chemistry, Benzamides pharmacokinetics, Benzamides pharmacology, Binding Sites, Biological Availability, Dogs, Hydroxamic Acids pharmacokinetics, Models, Molecular, Protease Inhibitors pharmacokinetics, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Swine, ADAM Proteins antagonists & inhibitors, Hydroxamic Acids chemistry, Hydroxamic Acids pharmacology, Protease Inhibitors chemistry, Protease Inhibitors pharmacology
- Abstract
Beta-benzamido hydroxamic acids were discovered as potent TACE inhibitors. A computer model was constructed to help understanding the binding activities and guiding SAR study. SAR optimization led to the discovery of compound 30 which met all in vitro and in vivo criteria for the program and was selected for further evaluation.
- Published
- 2008
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- View/download PDF
6. Design and identification of selective HER-2 sheddase inhibitors via P1' manipulation and unconventional P2' perturbations to induce a molecular metamorphosis.
- Author
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Yao W, Zhuo J, Burns DM, Li YL, Qian DQ, Zhang C, He C, Xu M, Shi E, Li Y, Marando CA, Covington MB, Yang G, Liu X, Pan M, Fridman JS, Scherle P, Wasserman ZR, Hollis G, Vaddi K, Yeleswaram S, Newton R, Friedman S, and Metcalf B
- Subjects
- ADAM Proteins metabolism, ADAM10 Protein, Amides chemical synthesis, Amides chemistry, Amides pharmacology, Amyloid Precursor Protein Secretases metabolism, Aza Compounds chemical synthesis, Aza Compounds chemistry, Aza Compounds pharmacology, Drug Design, Hydroxamic Acids chemical synthesis, Hydroxamic Acids pharmacology, Membrane Proteins metabolism, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacology, Protein Structure, Tertiary, Receptor, ErbB-2 metabolism, Spiro Compounds chemical synthesis, Spiro Compounds chemistry, Spiro Compounds pharmacology, Structure-Activity Relationship, Substrate Specificity, ADAM Proteins antagonists & inhibitors, Amyloid Precursor Protein Secretases antagonists & inhibitors, Hydroxamic Acids chemistry, Membrane Proteins antagonists & inhibitors, Protein Kinase Inhibitors chemistry, Receptor, ErbB-2 antagonists & inhibitors
- Abstract
In an effort to obtain a MMP selective and potent inhibitor of HER-2 sheddase (ADAM-10), the P1' group of a novel class of (6S,7S)-7-[(hydroxyamino)carbonyl]-6-carboxamide-5-azaspiro[2.5]octane-5-carboxylates was attenuated and the structure-activity relationships (SAR) will be discussed. In addition, it was discovered that unconventional perturbation of the P2' moiety could confer MMP selectivity, which was hypothesized to be a manifestation of the P2' group effecting global conformational changes.
- Published
- 2008
- Full Text
- View/download PDF
7. Pharmacokinetics and pharmacodynamics of DPC 333 ((2R)-2-((3R)-3-amino-3{4-[2-methyl-4-quinolinyl) methoxy] phenyl}-2-oxopyrrolidinyl)-N-hydroxy-4-methylpentanamide)), a potent and selective inhibitor of tumor necrosis factor alpha-converting enzyme in rodents, dogs, chimpanzees, and humans.
- Author
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Qian M, Bai SA, Brogdon B, Wu JT, Liu RQ, Covington MB, Vaddi K, Newton RC, Fossler MJ, Garner CE, Deng Y, Maduskuie T, Trzaskos J, Duan JJ, Decicco CP, and Christ DD
- Subjects
- ADAM17 Protein, Adult, Animals, Anti-Inflammatory Agents blood, Arthritis, Experimental blood, Arthritis, Experimental pathology, Dogs, Double-Blind Method, Endotoxemia blood, Endotoxemia chemically induced, Female, Humans, Lipopolysaccharides, Male, Mice, Mice, Inbred BALB C, Pan troglodytes, Quinolines blood, Rats, Rats, Inbred Strains, Synovial Fluid chemistry, Tumor Necrosis Factor-alpha antagonists & inhibitors, Tumor Necrosis Factor-alpha blood, ADAM Proteins antagonists & inhibitors, Anti-Inflammatory Agents pharmacokinetics, Anti-Inflammatory Agents therapeutic use, Arthritis, Experimental drug therapy, Endotoxemia drug therapy, Quinolines pharmacokinetics, Quinolines therapeutic use
- Abstract
DPC 333 ((2R)-2-((3R)-3-amino-3{4-[2-methyl-4-quinolinyl) methoxy] phenyl}-2-oxopyrrolidinyl)-N-hydroxy-4-methylpentanamide)) is a potent and selective inhibitor of tumor necrosis factor (TNF)-alpha-converting enzyme (TACE). It significantly inhibits lipopolysaccharide-induced soluble TNF-alpha production in blood from rodents, chimpanzee, and human, with IC(50) values ranging from 17 to 100 nM. In rodent models of endotoxemia, DPC 333 inhibited the production of TNF-alpha in a dose-dependent manner, with an oral ED(50) ranging from 1.1 to 6.1 mg/kg. Oral dosing of DPC 333 at 5.5 mg/kg daily for 2 weeks in a rat collagen antibody-induced arthritis model suppressed the maximal response by approximately 50%. DPC 333 was distributed widely to tissues including the synovium, the site of action for antiarthritic drugs. Pharmacokinetic and pharmacodynamic studies in chimpanzee revealed a systemic clearance of 0.4 l/h/kg, a V(ss) of 0.6 l/kg, an oral bioavailability of 17%, and an ex vivo IC(50) for the suppression of TNF-alpha production of 55 nM (n = 1). In a phase I clinical trial with male volunteers after single escalating doses of oral DPC 333, the terminal half-life was between 3 and 6 h and the ex vivo IC(50) for suppressing TNF-alpha production was 113 nM. Measurement of the suppression of TNF-alpha production ex vivo may serve as a good biomarker in evaluating the therapeutic efficacy of TACE inhibitors. Overall, the pharmacological profiles of DPC 333 support the notion that suppression of TNF-alpha with TACE inhibitors like DPC 333 may provide a novel approach in the treatment of various inflammatory diseases including rheumatoid arthritis, via control of excessive TNF-alpha production.
- Published
- 2007
- Full Text
- View/download PDF
8. Selective inhibition of ADAM metalloproteases as a novel approach for modulating ErbB pathways in cancer.
- Author
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Fridman JS, Caulder E, Hansbury M, Liu X, Yang G, Wang Q, Lo Y, Zhou BB, Pan M, Thomas SM, Grandis JR, Zhuo J, Yao W, Newton RC, Friedman SM, Scherle PA, and Vaddi K
- Subjects
- Animals, CHO Cells, Cells, Cultured, Cricetinae, Cricetulus, Humans, Mice, Mice, Inbred BALB C, Mice, Nude, Models, Biological, Neoplasms metabolism, Neoplasms pathology, Rats, Xenograft Model Antitumor Assays, ADAM Proteins antagonists & inhibitors, Neoplasms drug therapy, Oncogene Proteins v-erbB metabolism, Signal Transduction drug effects
- Abstract
Purpose: ErbB receptor signaling pathways are important regulators of cell fate, and their dysregulation, through (epi)genetic alterations, plays an etiologic role in multiple cancers. ErbB ligands are synthesized as membrane-bound precursors that are cleaved by members of the ADAM family of zinc-dependent metalloproteases. This processing, termed ectodomain shedding, is essential for the functional activation of ErbB ligands. Recent studies suggest that elevated levels of ErbB ligands may circumvent the effectiveness of ErbB-targeted therapeutics. Here, we describe the discovery and preclinical development of potent, selective inhibitors of ErbB ligand shedding., Experimental Design: A series of biochemical and cell-based assays were established to identify selective inhibitors of ErbB ligand shedding. The therapeutic potential of these compounds was assessed in multiple in vivo models of cancer and matrix metalloprotease-related toxicity., Results: INCB3619 was identified as a representative selective, potent, orally bioavailable small-molecule inhibitor of a subset of ADAM proteases that block shedding of ErbB ligands. Administration of INCB3619 to tumor-bearing mice reduced ErbB ligand shedding in vivo and inhibited ErbB pathway signaling (e.g., phosphorylation of Akt), tumor cell proliferation, and survival. Further, INCB3619 synergized with clinically relevant cancer therapeutics and showed no overt or compounding toxicities, including fibroplasia, the dose-limiting toxicity associated with broad-spectrum matrix metalloprotease inhibitors., Conclusions: Inhibition of ErbB ligand shedding offers a potentially novel and well-tolerated therapeutic strategy for the treatment of human cancers and is currently being evaluated in the clinic.
- Published
- 2007
- Full Text
- View/download PDF
9. Targeting ADAM-mediated ligand cleavage to inhibit HER3 and EGFR pathways in non-small cell lung cancer.
- Author
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Zhou BB, Peyton M, He B, Liu C, Girard L, Caudler E, Lo Y, Baribaud F, Mikami I, Reguart N, Yang G, Li Y, Yao W, Vaddi K, Gazdar AF, Friedman SM, Jablons DM, Newton RC, Fridman JS, Minna JD, and Scherle PA
- Subjects
- ADAM Proteins genetics, ADAM Proteins metabolism, ADAM17 Protein, Animals, Apoptosis drug effects, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung metabolism, Cell Line, Tumor, ErbB Receptors genetics, Female, Gefitinib, Gene Expression genetics, Humans, Ligands, Mice, Mice, Inbred BALB C, Mice, Nude, Models, Biological, Paclitaxel pharmacology, Piperidines therapeutic use, Protease Inhibitors pharmacology, Protease Inhibitors therapeutic use, Protein Kinase Inhibitors pharmacology, Quinazolines pharmacology, Spiro Compounds therapeutic use, Xenograft Model Antitumor Assays, ADAM Proteins antagonists & inhibitors, Carcinoma, Non-Small-Cell Lung drug therapy, ErbB Receptors metabolism, Piperidines pharmacology, Receptor, ErbB-3 metabolism, Signal Transduction drug effects, Spiro Compounds pharmacology
- Abstract
We describe here the existence of a heregulin-HER3 autocrine loop, and the contribution of heregulin-dependent, HER2-mediated HER3 activation to gefitinib insensitivity in non-small cell lung cancer (NSCLC). ADAM17 protein, a major ErbB ligand sheddase, is upregulated in NSCLC and is required not only for heregulin-dependent HER3 signaling, but also for EGFR ligand-dependent signaling in NSCLC cell lines. A selective ADAM inhibitor, INCB3619, prevents the processing and activation of multiple ErbB ligands, including heregulin. In addition, INCB3619 inhibits gefitinib-resistant HER3 signaling and enhances gefitinib inhibition of EGFR signaling in NSCLC. These results show that ADAM inhibition affects multiple ErbB pathways in NSCLC and thus offers an excellent opportunity for pharmacological intervention, either alone or in combination with other drugs.
- Published
- 2006
- Full Text
- View/download PDF
10. Selective inhibition of ADAM metalloproteases blocks HER-2 extracellular domain (ECD) cleavage and potentiates the anti-tumor effects of trastuzumab.
- Author
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Liu X, Fridman JS, Wang Q, Caulder E, Yang G, Covington M, Liu C, Marando C, Zhuo J, Li Y, Yao W, Vaddi K, Newton RC, Scherle PA, and Friedman SM
- Subjects
- Animals, Antibodies, Monoclonal, Humanized, Antineoplastic Agents therapeutic use, Apoptosis drug effects, Cell Division drug effects, Cell Line, Tumor, Female, Humans, Mice, Mice, Nude, Transplantation, Heterologous, Trastuzumab, ADAM Proteins antagonists & inhibitors, Antibodies, Monoclonal therapeutic use, Breast Neoplasms drug therapy, Receptor, ErbB-2 antagonists & inhibitors
- Abstract
The HER-2 receptor tyrosine kinase is an important regulator of cell proliferation and survival, and it is a clinically validated target of therapeutic intervention for HER-2 positive breast cancer patients. Its extracellular domain (ECD) is frequently cleaved by protease(s) in HER-2 overexpressing breast cancer patients, rendering the remaining membrane-bound portion (p95) a constitutively activated kinase. The presence of both serum ECD and cellular p95 protein has been linked to poor clinical outcome as well as reduced effectiveness of some therapeutic treatments. We have identified a series of potent, selective small molecule inhibitors of ADAM proteases, exemplified here by INCB003619, and demonstrate that these inhibitors effectively block HER-2 cleavage in HER-2 overexpressing human breast cancer cell lines. Intriguingly, when used in combination, INCB003619 dramatically enhances the antiproliferative activity of suboptimal doses of the anti-HER-2 antibody, trastuzumab, in HER-2 overexpressing/shedding breast cancer cell lines, accompanied by reduced ERK and AKT phosphorylation. Furthermore, INCB003619, in combination with trastuzumab, augments the pro-apoptotic and antiproliferative effects of the chemotherapeutic agent paclitaxel. Consistent with these in vitro data, INCB003619 reduces serum ECD levels and enhances the antitumor effect of trastuzumab in a xenograft tumor model derived from the HER-2 overexpressing BT-474 breast cancer cell line. Collectively, these findings suggest that blocking HER-2 cleavage with selective ADAM inhibitors may represent a novel therapeutic approach for treating HER-2 overexpressing breast cancer patients.
- Published
- 2006
- Full Text
- View/download PDF
11. Synthesis and structure-activity relationship of a novel, achiral series of TNF-alpha converting enzyme inhibitors.
- Author
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Gilmore JL, King BW, Harris C, Maduskuie T, Mercer SE, Liu RQ, Covington MB, Qian M, Ribadeneria MD, Vaddi K, Trzaskos JM, Newton RC, Decicco CP, and Duan JJ
- Subjects
- ADAM17 Protein, Animals, Cell Line, Cyclization, Humans, Mice, Protease Inhibitors chemistry, Protease Inhibitors pharmacokinetics, Stereoisomerism, Structure-Activity Relationship, ADAM Proteins antagonists & inhibitors, Protease Inhibitors chemical synthesis, Protease Inhibitors pharmacology
- Abstract
A novel series of achiral TNF-alpha converting enzyme (TACE) inhibitors has been discovered. These compounds exhibited activities from 0.35 to 11nM in a porcine TACE assay and inhibited TNF-alpha production in an LPS-stimulated whole blood assay with an IC(50) value of 23nM for the most potent one. They also have excellent selectivities over related metalloproteases including aggrecanases.
- Published
- 2006
- Full Text
- View/download PDF
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