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 T Hunt; 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

doi:10.1021/jm000248z

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.

Authors

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.

MeSH terms

3T3 Cells
Alkyl and Aryl Transferases / antagonists & inhibitors*
Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology
Benzodiazepines / chemical synthesis*
Benzodiazepines / chemistry
Benzodiazepines / pharmacokinetics
Benzodiazepines / pharmacology
Biological Availability
Cell Line, Transformed
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacokinetics
Enzyme Inhibitors / pharmacology
Farnesyltranstransferase
Genes, ras
Humans
Imidazoles / chemical synthesis*
Imidazoles / chemistry
Imidazoles / pharmacokinetics
Imidazoles / pharmacology
Mice
Mice, Inbred BALB C
Rats
Stereoisomerism
Structure-Activity Relationship
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Enzyme Inhibitors
Imidazoles
Benzodiazepines
Alkyl and Aryl Transferases
Farnesyltranstransferase
7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine