Farnesyl protein transferase inhibitor ZARNESTRA R115777 - history of a discovery.
R115777 (R)-6-amino[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone is a potent and selective inhibitor of farnesyl protein transferase with significant antitumor effects in vivo subsequent to oral administration in mice. Taking its roots into Janssen's ketoconazole and retinoic acid catabolism programs, our interest into Ras prenylation process led us stepwise to identify the key structural features of R115777. Methodology, structure activity relationships, and pharmacology will be presented. R115777 is currently in phase III clinical evaluation.
Venet
Marc
M
Johnson & Johnson Pharmaceutical Research, Campus de Maigremont, BP 615, 27106 Val de Reuil Cedex, France. marc.venet@libertysurf.fr
End
David
D
Angibaud
Patrick
P
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy; D017368:Protein Prenylation / Q000187:drug effects; D015363:Quinolones / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D015363:Quinolones; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; C402769:tipifarnib