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

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 f...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2011-06, Vol.54 (11), p.3756-3767
Main Authors: Kazmierski, Wieslaw M, Anderson, Don L, Aquino, Christopher, Chauder, Brian A, Duan, Maosheng, Ferris, Robert, Kenakin, Terrence, Koble, Cecilia S, Lang, Dan G, Mcintyre, Maggie S, Peckham, Jennifer, Watson, Christian, Wheelan, Pat, Spaltenstein, Andrew, Wire, Mary B, Svolto, Angilique, Youngman, Michael
Format: Article
Language:English
Subjects:
Animals
Anti-HIV Agents - chemical synthesis
Anti-HIV Agents - chemistry
Anti-HIV Agents - metabolism
Anti-HIV Agents - pharmacology
Area Under Curve
Azabicyclo Compounds - chemical synthesis
Azabicyclo Compounds - chemistry
Azabicyclo Compounds - metabolism
Azabicyclo Compounds - pharmacology
CCR5 Receptor Antagonists
Dogs
Drug Design
Ether-A-Go-Go Potassium Channels - antagonists & inhibitors
Ether-A-Go-Go Potassium Channels - genetics
Ether-A-Go-Go Potassium Channels - metabolism
Haplorhini
HIV-1 - drug effects
Humans
Piperidines - chemical synthesis
Piperidines - chemistry
Piperidines - metabolism
Piperidines - pharmacology
Rats
Structure-Activity Relationship
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Summary: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).
ISSN:0022-2623
1520-4804
DOI:10.1021/jm200279v