Influence of novel heterocyclic sidechains on the SAR of a series of 3-[6-(4-substituted-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridin-2-one inhibitors of the IGF-1R kinase

MEDI 120

David B. Frennesson, david.frennesson@bms.com1, Mark G. Saulnier1, Charles Struzynski2, David Langley3, Upender Velaparthi1, Peiying Liu, peiying.liu@bms.com1, Kurt Zimmermann, Kurt.Zimmermann@bms.com4, Xiaopeng Sang, xiaopeng.sang@bms.com2, Francis Y. Lee5, Joan Carboni6, Aixin Li6, Ann Greer6, Praveen Balimane6, Zheng Yang7, Chiehying Chang, John Sack8, George L. Trainor9, Mark D. Wittman, mark.wittman@bms.com4, Dolatrai M. Vyas2, Ricardo Attar, Ricardo.Attar@bms.com6, and Marco Gottardis10. (1) Discovery Chemistry, Bristol Myers Squibb Co, Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, (2) Discovery Chemistry, Bristol Myers Squibb Co, Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, (3) Computer-Assisted Drug Design, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492-7660, (4) Bristol-Myers Squibb Co, Pharmaceutical Research Institute, Wallingford, CT, 5 Research Parkway, Wallingford, CT 06492, (5) Oncology Drug Discovery, Bristol Myers Squibb Co, Pharmaceutical Research Institute, Route 206 and Province Line Rd, Princeton, NJ 08543, (6) Bristol-Myers Squibb Co, Pharmaceutical Research Institute, Princeton, NJ, Rt 206 and Province Line Rd, Princeton, NJ 08543, (7) Department of Metabolism and Pharmacokinetics, Bristol Myers Squibb Pharmaceutical Research Institute, 5 Research ParkWay, Wallingford, CT 06492, (8) Department of Macromolecular Structure, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, NJ 08543-4000, (9) Discovery Chemistry Department, Bristol-Myers Squibb Co, P.O. Box 4000, Princeton, NJ 08543-4000, (10) Oncology Drug Discovery, Bristol-Myers Squibb Co, Pharmaceutical Research Institute, Princeton, NJ, Route 206 and Province Line Rd, Princeton, NJ 08543
Signaling through the insulin-like growth factor I receptor (IGF-1R) results in the activation of two major downstream signaling cascades, the RAS/Raf/MAP kinase pathway (mitogenesis) and the PI-3 kinase pathway (anti-apoptosis). Binding of the IGF-I ligand to the extracellular ligand binding domain of the receptor results in receptor autophosphorylation and activation of the kinase activity. Epidemiological studies have shown that elevated IGF-I levels correlate with increased risk of developing colon, breast, prostate, and lung tumors. Thus antagonism of IGF-IR signaling is an appealing target for novel antitumor agents. In this context we have previously reported biology on our prototypical lead BMS-535924. In an ongoing effort toward further lead optimization we have identified a series of 3-[6-(4-substituted-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridin-2-ones employing novel heterocyclic sidechains. Among these several analogs have emerged as potent IGF-1R kinase inhibitors with in vivo antitumor activity in an IGF-1R-dependent tumor model (IGF-1R Sal). Relevant chemistry and SAR will be presented.
 

General Poster Session
7:00 PM-9:00 PM, Sunday, 10 September 2006 Moscone Center -- Hall D, Poster

Division of Medicinal Chemistry

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