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.
F George Njoroge  1 ,  Bancha Vibulbhan ,  Xiongwei Shi ,  Corey Strickland ,  Paul Kirschmeier ,  Robert Bishop ,  Amin Nomeir ,  Viyyoor Girijavallabhan
Affiliations
  • 1. Schering-Plough Research Institute, 2015 Galloping Hill Road, K-15-3-3545, Kenilworth, NJ 07033, USA. [email protected]
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.