1. Academic Validation
  2. Amino derivatives of indole as potent inhibitors of isoprenylcysteine carboxyl methyltransferase

Amino derivatives of indole as potent inhibitors of isoprenylcysteine carboxyl methyltransferase

  • J Med Chem. 2010 Oct 14;53(19):6838-50. doi: 10.1021/jm1002843.
Mei-Lin Go 1 Jo Lene Leow Suresh Kumar Gorla Andreas Peter Schüller Mei Wang Patrick J Casey
Affiliations

Affiliation

  • 1 Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543. phagoml@nus.edu.sg
Abstract

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.

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