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).
MeSH terms
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Animals
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Anti-HIV Agents / chemical synthesis
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Anti-HIV Agents / chemistry*
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Anti-HIV Agents / metabolism
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Anti-HIV Agents / pharmacology*
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Area Under Curve
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Azabicyclo Compounds / chemical synthesis
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Azabicyclo Compounds / chemistry*
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Azabicyclo Compounds / metabolism
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Azabicyclo Compounds / pharmacology*
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Benzimidazoles
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CCR5 Receptor Antagonists*
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Dogs
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Drug Design
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
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Ether-A-Go-Go Potassium Channels / genetics
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Ether-A-Go-Go Potassium Channels / metabolism
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HIV-1 / drug effects*
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Haplorhini
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Humans
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Piperidines / chemical synthesis
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Piperidines / chemistry*
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Piperidines / metabolism
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Piperidines / pharmacology*
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Rats
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Structure-Activity Relationship
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Sulfonamides
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Tropanes
Substances
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Anti-HIV Agents
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Azabicyclo Compounds
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Benzimidazoles
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CCR5 Receptor Antagonists
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Ether-A-Go-Go Potassium Channels
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GSK 163929
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Piperidines
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Sulfonamides
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Tropanes