Referenced in: none

Automatically associated channels: Kv11.1 , SK1

Title: Novel 4,4-disubstituted piperidine-based C-C chemokine receptor-5 inhibitors with high potency against human immunodeficiency virus-1 and an improved human ether-a-go-go related gene (hERG) profile.

Authors: Wieslaw M Kazmierski, Don L Anderson, Christopher Aquino, Brian A Chauder, Maosheng Duan, Robert Ferris, Terrence Kenakin, Cecilia S Koble, Dan G Lang, Maggie S McIntyre, Jennifer Peckham, Christian Watson, Pat Wheelan, Andrew Spaltenstein, Mary B Wire, Angilique Svolto, Michael Youngman

Journal, date & volume: J. Med. Chem., 2011 Jun 9 , 54, 3756-67

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/21539377

Abstract
We recently described ( J. Med. Chem. 2008 , 51 , 6538 - 6546 ) a novel class of CCR5 antagonists with strong anti-HIV potency. Herein, we detail SAR converting leads 1 and 2 to druglike molecules. The pivotal structural motif enabling this transition was the secondary sulfonamide substituent. Further fine-tuning of the substituent pattern in the sulfonamide paved the way to enhancing potency and bioavailability and minimizing hERG inhibition, resulting in discovery of clinical compound 122 (GSK163929).