Amino derivatives of indole as potent inhibitors of isoprenylcysteine carboxyl methyltransferase.

Journal Article (Journal Article)

The enzyme isoprenylcysteine carboxyl methyltransferase (Icmt) plays an important role in the post-translational modification of proteins that are involved in the regulation of cell growth. The indole acetamide cysmethynil is by far the most potent and widely investigated Icmt inhibitor, but it has modest antiproliferative activity and may have pharmacokinetic limitations due to its lipophilic character. We report here that cysmethynil can be structurally modified to give analogues that are as potent in inhibiting Icmt but with significantly greater antiproliferative activity. Key modifications were the replacement of the acetamide side chain by tertiary amino groups, the n-octyl side chain by isoprenyl and the 5-m-tolyl ring by fluorine. Moreover, these analogues have lower lipophilicities that could lead to improved pharmacokinetic profiles.

Full Text

Duke Authors

Cited Authors

  • Go, M-L; Leow, JL; Gorla, SK; Schüller, AP; Wang, M; Casey, PJ

Published Date

  • October 14, 2010

Published In

Volume / Issue

  • 53 / 19

Start / End Page

  • 6838 - 6850

PubMed ID

  • 20809634

Electronic International Standard Serial Number (EISSN)

  • 1520-4804

Digital Object Identifier (DOI)

  • 10.1021/jm1002843


  • eng

Conference Location

  • United States