New class of azaheptapyridine FPT inhibitors as potential cancer therapy agents.
Tertiary hydroxyl class of C-imidazole bridgehead azaheptapyridine FPT inhibitors were prepared in an attempt to block in vivo oxidation of secondary hydroxyl series. One representative compound 5a exhibited potent enzyme (IC50=1.4 nM) and cellular activities (soft agar IC50=1.3 nM) with excellent oral pharmacokinetic profiles in rats, mice, monkeys and dogs. The in vivo study in wap-ras TG mouse models showed dose dependent tumor growth inhibition and regression.
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA. Electronic address: hughzhu@hotmail.com.
Hugh Y
HY
Zhu
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Jagdish
J
Desai
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Alan B
AB
Cooper
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
James
J
Wang
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Dinananth F
DF
Rane
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Paul
P
Kirschmeier
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Corey
C
Strickland
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Ming
M
Liu
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Amin A
AA
Nomeir
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Viyyoor M
VM
Girijavallabhan
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000882:Haplorhini; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001372:Aza Compounds; D004791:Enzyme Inhibitors; D011725:Pyridines; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase
FPT inhibitors