N-(cycloalkylamino)acyl-2-aminothiazole inhibitors of cyclin-dependent kinase 2. N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide (BMS-387032), a highly efficacious and selective antitumor agent

  • J Med Chem. 2004 Mar 25;47(7):1719-28. doi: 10.1021/jm0305568.
Raj N Misra  1 ,  Hai-yun Xiao ,  Kyoung S Kim ,  Songfeng Lu ,  Wen-Ching Han ,  Stephanie A Barbosa ,  John T Hunt ,  David B Rawlins ,  Weifang Shan ,  Syed Z Ahmed ,  Ligang Qian ,  Bang-Chi Chen ,  Rulin Zhao ,  Mark S Bednarz ,  Kristen A Kellar ,  Janet G Mulheron ,  Roberta Batorsky ,  Urvashi Roongta ,  Amrita Kamath ,  Punit Marathe ,  Sunanda A Ranadive ,  John S Sack ,  John S Tokarski ,  Nikola P Pavletich ,  Francis Y F Lee ,  Kevin R Webster ,  S David Kimball
Affiliations
  • 1. Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, New Jersey 08543-4000, USA. [email protected]
PMID: 15027863 DOI: 10.1021/jm0305568
Abstract

N-Acyl-2-aminothiazoles with nonaromatic acyl side chains containing a basic amine were found to be potent, selective inhibitors of CDK2/cycE which exhibit antitumor activity in mice. In particular, compound 21 [N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, BMS-387032], has been identified as an ATP-competitive and CDK2-selective inhibitor which has been selected to enter Phase 1 human clinical trials as an antitumor agent. In a cell-free enzyme assay, 21 showed a CDK2/cycE IC(50) = 48 nM and was 10- and 20-fold selective over CDK1/cycB and CDK4/cycD, respectively. It was also highly selective over a panel of 12 unrelated Kinases. Antiproliferative activity was established in an A2780 cellular cytotoxicity assay in which 21 showed an IC(50) = 95 nM. Metabolism and pharmacokinetic studies showed that 21 exhibited a plasma half-life of 5-7 h in three species and moderately low protein binding in both mouse (69%) and human (63%) serum. Dosed orally to mouse, rat, and dog, 21 showed 100%, 31%, and 28% bioavailability, respectively. As an antitumor agent in mice, 21 administered at its maximum-tolerated dose exhibited a clearly superior efficacy profile when compared to flavopiridol in both an IP/IP P388 murine tumor model and in a s.c./i.p. A2780 human ovarian carcinoma xenograft model.