2. Academic Validation
  3. Discovery of (R)-7-cyano-2,3,4, 5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine (BMS-214662), a farnesyltransferase inhibitor with potent preclinical antitumor activity

Discovery of (R)-7-cyano-2,3,4, 5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine (BMS-214662), a farnesyltransferase inhibitor with potent preclinical antitumor activity

  • J Med Chem. 2000 Oct 5;43(20):3587-95. doi: 10.1021/jm000248z.
J T Hunt 1,  C Z Ding,  R Batorsky,  M Bednarz,  R Bhide,  Y Cho,  S Chong,  S Chao,  J Gullo-Brown,  P Guo,  S H Kim,  F Y Lee,  K Leftheris,  A Miller,  T Mitt,  M Patel,  B A Penhallow,  C Ricca,  W C Rose,  R Schmidt,  W A Slusarchyk,  G Vite,  V Manne
Affiliations

Affiliation

  • 1 Department of Oncology Chemistry, Chemistry Core Resources, Metabolism and Pharmacokinetics, and Oncology Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA. john.hunt@bms.com
PMID: 11020273 DOI: 10.1021/jm000248z
Abstract

Continuing structure-activity studies were performed on the 2,3,4, 5-tetrahydro-1-(imidazol-4-ylalkyl)-1,4-benzodiazepine farnesyltransferase (FT) inhibitors. These studies demonstrated that a 3(R)-phenylmethyl group, a hydrophilic 7-cyano group, and a 4-sulfonyl group bearing a variety of substituents provide low-nanomolar FT inhibitors with cellular activity at concentrations below 100 nM. Maximal in vivo activity in the mutated K-Ras bearing HCT-116 human colon tumor model was achieved with analogues carrying hydrophobic side chains such as propyl, phenyl, or thienyl attached to the N-4 sulfonyl group. Several such compounds achieved curative efficacy when given orally in this model. On the basis of its excellent preclinical antitumor activity and promising pharmacokinetics, compound 20 (BMS-214662, (R)-7-cyano-2,3,4, 5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thie nyl sulfonyl)-1H-1,4-benzodiazepine) has been advanced into human clinical trials.

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