Amino Derivatives of Indole As Potent Inhibitors of Isoprenylcysteine Carboxyl Methyltransferase

• Published in: Journal of medicinal chemistry 2010-10, Vol.53 (19), p.6838-6850
• Main Authors: Go, Mei-Lin, Leow, Jo Lene, Gorla, Suresh Kumar, Schüller, Andreas Peter, Wang, Mei, Casey, Patrick J
• Format: Article
• Language: English
• Subjects: Amines - chemical synthesis; Amines - chemistry; Amines - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Drug Screening Assays, Antitumor; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Protein Methyltransferases - antagonists & inhibitors; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm1002843

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.