2. Academic Validation
  3. 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

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

Affiliation

  • 1 GlaxoSmithKline, Research Triangle Park, NC 27709, USA. kazmierski@gsk.com
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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