MEDI 295

2-Aminothiazole: A novel template for the discovery of Dasatinib (BMS-354825), a pan Src/Abl kinase inhibitor

Jagabandhu Das, jagabandhu.das@bms.com¹, Ping Chen², Louis J. Lombardo, louis.lombardo@bms.com³, Francis Y. Lee⁴, Derek Norris⁵, Robert V. Moquin, robert.moquin@bms.com¹, James Lin¹, Zhongqi Shen⁵, Kamelia Behnia⁶, Ramesh Padmanabha⁷, Lynda S. Carter⁷, Stephen Castaneda⁸, Lyndon Cornelius⁵, Arthur M. Doweyko, arthur.doweyko@bms.com⁹, Craig R. Fairchild¹⁰, John T. Hunt¹¹, Ivan Inigo¹², Amrita Kamath¹³, David Kan¹², Punit Marathe⁸, Suhong Pang⁸, Sidney Pitt¹⁴, Gary Schieven¹⁵, Kim McIntyre¹⁵, David Shuster¹⁵, Kathleen Gillooly¹⁵, Robert Schmidt¹⁶, John Tokarski¹⁷, Mei-Li Wen⁸, Robert Borzilleri¹⁶, John Wityak¹⁶, and Joel C Barrish, barrishj@bms.com¹⁸. (1) Lawrenceville Discovery Chemistry, Bristol-Myers Squibb PRI, Provinceline Rd and Route 206, P.O. Box 4000, Princeton, NJ 08543-4000, (2) Pharmaceutical Research Institute, Bristol-Myers Squibb, P. O. Box 4000, Princeton, NJ 08543, (3) Discovery Chemistry, Bristol-Myers Squibb, P.O. Box 4000, Princeton, NJ 08543-4000, (4) Oncology Drug Discovery, Bristol Myers Squibb Co, Pharmaceutical Research Institute, Route 206 and Province Line Rd, Princeton, NJ 08543, (5) Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, P. O. Box 4000, Princeton, NJ 08543-4000, (6) Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb, (7) Bristol-Myers Squibb Pharmaceutical Research Institute, wallingford, CT, (8) Bristol-Myers Squibb Pharmaceutical Research Institute, Route 206 and Provinceline Road, Princeton, NJ 08543-4000, (9) Pharmaceutical Research Institute, CADD, Bristol-Myers Squibb PRI, Rte. 206 and Provinceline Road, Princeton, NJ 08543, (10) Pharmaceutical Research Institute, Bristol-Myers Squibb Co, Princeton, NJ 08543, (11) Oncology Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, P. O. Box 4000, Princeton, NJ 08543-4000, (12) Experimental Therapeutics, Bristol-Myers Squibb PRI, CN 4000, Princeton, NJ 08543-4000, (13) PCO, Bristol-Myers Squibb PRI, PO Box 4000, Princeton, NJ 08543-4000, (14) Department of Immunology, Pharmaceutical Research Institute, Bristol-Myers Squibb, P.O. Box 4000, Princeton, NJ 08543-4000, (15) Discovery Biology, Pharmaceutical Research Institute, Bristol-Myers Squibb, P.O. Box 4000, Princeton, NJ 08543-4000, (16) Discovery Chemistry, Pharmaceutical Research Institute, Bristol-Myers Squibb, P. O. Box 4000, Route 206 and Provinceline, Princeton, NJ 08543-4000, (17) CAD Group, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, NJ 08543-4000, (18) Discovery Chemistry, Bristol-Myers Squibb Company, P. O. Box 4000, Princeton, NJ 08543-4000

2-Aminothiazole (1) was discovered as a novel Src family kinase inhibitor template through screening of our internal compound collection. Optimization through successive SAR iterations identified analogs 2 and 3 as pan-Src/Abl inhibitors with nanomolar to sub-nanomolar potencies in biochemical and cellular assays. Using molecular modeling, a putative binding model for Lck inhibition by this class of compounds was also constructed. The in vivo efficacy of this class of inhibitors was demonstrated with 2 in an acute model of inflammation (LPS-induced TNFτ production) when dosed orally at 60 mg/kg, 2 h prior to LPS administration and a chronic model of adjuvant arthritis in rats with established disease when administered orally at 0.3 and 3 mg/kg, twice daily. Furthermore, based on its exquisite biochemical potency against Src family and Bcr-Abl kinases, broad spectrum antiproliferative activity against several hematological and solid tumor cell lines, modest protein binding and sustained plasma exposure , 3 was selected for in vivo efficacy studies in a K562 xenograft model of Chronic Myelogenous Leukemia (CML). Dasatinib (3) is currently in clinical trials for the treatment of CML.

General Oral Session
1:30 PM-4:50 PM, Tuesday, 12 September 2006 Moscone Center -- Room 103, Oral

Division of Medicinal Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006