Design and synthesis of piperidine farnesyltransferase inhibitors with reduced glucuronidation potential |
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Authors: | Tanaka Rieko Rubio Almudena Harn Nancy K Gernert Douglas Grese Timothy A Eishima Jun Hara Mitsunobu Yoda Nobuyuki Ohashi Rui Kuwabara Takashi Soga Shiro Akinaga Shiro Nara Shinji Kanda Yutaka |
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Institution: | Pharmaceutical Research Center, Kyowa Hakko Kogyo Co. Ltd, 1188 Shimotogari, Nagaizumi-cho, Shizuoka 411-8731, Japan. |
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Abstract: | 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. |
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