Referenced in: none

Automatically associated channels: Kv11.1

Title: Kinesin spindle protein (KSP) inhibitors. Part 3: synthesis and evaluation of phenolic 2,4-diaryl-2,5-dihydropyrroles with reduced hERG binding and employment of a phosphate prodrug strategy for aqueous solubility.

Authors: Robert M Garbaccio, Mark E Fraley, Edward S Tasber, Christy M Olson, William F Hoffman, Kenneth L Arrington, Maricel Torrent, Carolyn A Buser, Eileen S Walsh, Kelly Hamilton, Michael D Schaber, Christine Fernandes, Robert B Lobell, Weikang Tao, Vicki J South, Youwei Yan, Lawrence C Kuo, Thomayant Prueksaritanont, Donald E Slaughter, Cathy Shu, David C Heimbrook, Nancy E Kohl, Hans E Huber, George D Hartman

Journal, date & volume: Bioorg. Med. Chem. Lett., 2006 Apr 1 , 16, 1780-3

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/16439122

Abstract
2,4-Diaryl-2,5-dihydropyrroles have been discovered to be novel, potent and water-soluble inhibitors of KSP, an emerging therapeutic target for the treatment of cancer. A potential concern for these basic KSP inhibitors (1 and 2) was hERG binding that can be minimized by incorporation of a potency-enhancing C2 phenol combined with neutral N1 side chains. Aqueous solubility was restored to these, and other, non-basic inhibitors, through a phosphate prodrug strategy.