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

  • J Med Chem. 2011 Jun 9;54(11):3756-67. doi: 10.1021/jm200279v.
Wieslaw M Kazmierski  1 ,  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
Affiliations
PMID: 21539377 DOI: 10.1021/jm200279v
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).

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