Bridgehead modification of trihalocycloheptabenzopyridine leads to a potent farnesyl protein transferase inhibitor with improved oral metabolic stability

F George Njoroge; Bancha Vibulbhan; Xiongwei Shi; Corey Strickland; Paul Kirschmeier; Robert Bishop; Amin Nomeir; Viyyoor Girijavallabhan

doi:10.1016/j.bmcl.2004.09.020

Bridgehead modification of trihalocycloheptabenzopyridine leads to a potent farnesyl protein transferase inhibitor with improved oral metabolic stability

Bioorg Med Chem Lett. 2004 Dec 6;14(23):5899-902. doi: 10.1016/j.bmcl.2004.09.020.

Authors

F George Njoroge¹, Bancha Vibulbhan, Xiongwei Shi, Corey Strickland, Paul Kirschmeier, Robert Bishop, Amin Nomeir, Viyyoor Girijavallabhan

Affiliation

¹ Schering-Plough Research Institute, 2015 Galloping Hill Road, K-15-3-3545, Kenilworth, NJ 07033, USA. george.njoroge@spcorp.com

PMID: 15501065
DOI: 10.1016/j.bmcl.2004.09.020

Abstract

Modification of the ethano bridge of the core structure of the antitumor agent, SARASAR (SCH66336) with concomitant introduction of a sulfonamide moiety off the distal piperidine afforded inhibitor 9-(S-), a compound with greatly improved PK profile. Other compounds with enhanced FPTase inhibitory activity were obtained as exemplified by amide 10-(S-) and urea 11-(S-): these compounds demonstrated activity in picomolar range.

MeSH terms

Administration, Oral
Alkyl and Aryl Transferases / antagonists & inhibitors*
Alkyl and Aryl Transferases / metabolism
Drug Stability
Enzyme Inhibitors / administration & dosage
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / metabolism
Molecular Conformation
Protein Binding / physiology
Pyridines / administration & dosage
Pyridines / chemistry*
Pyridines / metabolism

Substances

Enzyme Inhibitors
Pyridines
Alkyl and Aryl Transferases
p21(ras) farnesyl-protein transferase