Design and synthesis of piperidine farnesyltransferase inhibitors with reduced glucuronidation potential.
The design and synthesis of a novel piperidine series of farnesyltransferase (FTase) inhibitors with reduced potential for metabolic glucuronidation are described. The various substitution and exchange of the phenyl group at the C-2 position of the previously described 2-(4-hydroxy)phenyl-3-nitropiperidine 1a (FTase IC(50)=5.4nM) resulted in metabolically stable compounds with potent FTase inhibition (14a IC(50)=4.3nM, 20a IC(50)=3.0nM, and 50a IC(50)=16nM). Molecular modeling studies of these compounds complexed with FTase and farnesyl pyrophosphate are also described.
Tanaka
Rieko
R
Pharmaceutical Research Center, Kyowa Hakko Kogyo Co. Ltd, 1188 Shimotogari, Nagaizumi-cho, Shizuoka 411-8731, Japan.
Rubio
Almudena
A
Harn
Nancy K
NK
Gernert
Douglas
D
Grese
Timothy A
TA
Eishima
Jun
J
Hara
Mitsunobu
M
Yoda
Nobuyuki
N
Ohashi
Rui
R
Kuwabara
Takashi
T
Soga
Shiro
S
Akinaga
Shiro
S
Nara
Shinji
S
Kanda
Yutaka
Y
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020719:Glucuronides / Q000378:metabolism*; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017368:Protein Prenylation; D051381:Rats; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D020719:Glucuronides; D010880:Piperidines; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase