Novel 4,4-Disubstituted Piperidine-Based C鈥揅 Chemokine Receptor-5 Inhibitors with High Potency against Human Immunodeficiency Virus-1 and an Improved human Ether-a-go-go Related Gene (hERG) Profile
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- 作者：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
- 刊名：Journal of Medicinal Chemistry
- 出版年：2011
- 出版时间：June 9, 2011
- 年：2011
- 卷：54
- 期：11
- 页码：3756-3767
- 全文大小：1287K
- 年卷期：v.54,no.11(June 9, 2011)
- ISSN：1520-4804
文摘
We recently described ( J. Med. Chem.pan class="NLM_x"> pan>2008pan class="NLM_x">, pan>51pan class="NLM_x">, pan>6538鈭?546) 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).