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Jagabandhu Das,
Ping Chen,
Derek Norris,
Ramesh Padmanabha,
James Lin,
Robert V Moquin,
Zhongqi Shen,
Lynda S Cook,
Arthur M Doweyko,
Sidney Pitt, [......],
Ding Ren Shen, Qiong Fang,
Henry F de Fex,
Kim W McIntyre,
David J Shuster,
Kathleen M Gillooly,
Kamelia Behnia,
Gary L Schieven,
John Wityak,
Joel C Barrish
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ABSTRACT: 2-aminothiazole (1) was discovered as a novel Src family kinase inhibitor template through screening of our internal compound collection. Optimization through successive structure-activity relationship iterations identified analogs 2 (Dasatinib, BMS-354825) and 12m as pan-Src inhibitors with nanomolar to subnanomolar potencies in biochemical and cellular assays. Molecular modeling was used to construct a putative binding model for Lck inhibition by this class of compounds. The framework of key hydrogen-bond interactions proposed by this model was in agreement with the subsequent, published crystal structure of 2 bound to structurally similar Abl kinase. The oral efficacy of this class of inhibitors was demonstrated with 12m in inhibiting the proinflammatory cytokine IL-2 ex vivo in mice (ED50 approximately 5 mg/kg) and in reducing TNF levels in an acute murine model of inflammation (90% inhibition in LPS-induced TNFalpha production when dosed orally at 60 mg/kg, 2 h prior to LPS administration). The oral efficacy of 12m was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally at 0.3 and 3 mg/kg twice daily. Dasatinib (2) is currently in clinical trials for the treatment of chronic myelogenous leukemia.
Journal of Medicinal Chemistry 12/2006; 49(23):6819-32. · 5.25 Impact Factor
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John Wityak,
Jagabandhu Das,
Robert V Moquin,
Zhongqi Shen,
James Lin,
Ping Chen,
Arthur M Doweyko,
Sidney Pitt,
Suhong Pang,
Ding Ren Shen, Qiong Fang,
Henry F de Fex,
Gary L Schieven,
Steven B Kanner,
Joel C Barrish
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ABSTRACT: A novel series of 2-amino-5-carboxamidothiazoles were identified as inhibitors of Lck. Structure-activity studies demonstrate the structural requirements for potent Lck activity. Cyclopropylamide 11d is a potent Lck inhibitor having sub-micromolar activity in a PBL proliferation assay.
Bioorganic & Medicinal Chemistry Letters 12/2003; 13(22):4007-10. · 2.55 Impact Factor
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Jagabandhu Das,
Robert V Moquin,
James Lin,
Chunjian Liu,
Arthur M Doweyko,
Henry F DeFex, Qiong Fang,
Suhong Pang,
Sidney Pitt,
Ding Ren Shen,
Gary L Schieven,
Joel C Barrish,
John Wityak
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ABSTRACT: A series of structurally novel benzothiazole based small molecule inhibitors of p56(lck) was prepared to elucidate their structure-activity relationships (SAR), selectivity and cell activity in the T-cell proliferation assay. BMS-350751 (2) and BMS-358233 (3) are identified as potent Lck inhibitors with excellent cellular activities against T-cell proliferation.
Bioorganic & Medicinal Chemistry Letters 09/2003; 13(15):2587-90. · 2.55 Impact Factor
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Jagabandhu Das,
James Lin,
Robert V Moquin,
Zhongqi Shen,
Steven H Spergel,
John Wityak,
Arthur M Doweyko,
Henry F DeFex, Qiong Fang,
Suhong Pang,
Sidney Pitt,
Ding Ren Shen,
Gary L Schieven,
Joel C Barrish
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ABSTRACT: A series of structurally novel benzothiazole based small molecule inhibitors of p56(lck) were prepared to elucidate their structure-activity relationships (SARs), selectivity and cell activity in the T-cell proliferation assay. BMS-243117 (compound 2) is identified as a potent, and selective Lck inhibitor with good cellular activity (IC(50)=1.1 microM) against T-cell proliferation.
Bioorganic & Medicinal Chemistry Letters 08/2003; 13(13):2145-9. · 2.55 Impact Factor
