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Discovery and structure-activity relationships of novel piperidine inhibitors of farnesyltransferase.

Abstract：

:A novel piperidine series of farnesyltransferase (FTase) inhibitors is described. Systematic medicinal chemistry studies starting with the lead compound, discovered from a 5-nitropiperidin-2-one combinatorial library, resulted in a potent series of novel FTase inhibitors. We found that all of four substituents of the piperidine core played an important role for FTase inhibition. A 10-fold increase in potency was observed by changing the piperidine-2-one core to the corresponding piperidine core. This class of compounds was found to inhibit farnesyltransferase in a Ras competitive manner. Optical resolution of several potent inhibitors revealed that the (+)-enantiomers showed potent farnesyltransferase inhibition. (+)-8 inhibited FTase with an IC(50) of 1.9 nM.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Nara S,Tanaka R,Eishima J,Hara M,Takahashi Y,Otaki S,Foglesong RJ,Hughes PF,Turkington S,Kanda Y

doi

10.1021/jm020522k

keywords:

subject

Has Abstract

pub_date

2003-06-05 00:00:00

pages

2467-73

issue

12

eissn

0022-2623

issn

1520-4804

journal_volume

46

pub_type

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