Piperazine-based CCR5 antagonists as HIV-1 inhibitors. IV. Discovery of 1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]- 4-[4-[2-methoxy-1(R)-4-(trifluoromethyl)phenyl]ethyl-3(S)-methyl-1-piperazinyl]- 4-methylpiperidine (Sch-417690/Sch-D), a potent, highly selective, and orally bioavailable CCR5 antagonist

The nature and the size of the benzylic substituent are shown to be the key to controlling receptor selectivity (CCR5 vs M1, M2) and potency in the title compounds. Optimization of the lead benzylic methyl compound 3 led to the methoxymethyl analogue 30, which had excellent receptor selectivity and...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2004-05, Vol.47 (10), p.2405
Main Authors: Tagat, Jayaram R, McCombie, Stuart W, Nazareno, Dennis, Labroli, Marc A, Xiao, Yushi, Steensma, Ruo W, Strizki, Julie M, Baroudy, Bahige M, Cox, Kathleen, Lachowicz, Jean, Varty, Geoffrey, Watkins, Robert
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Anti-HIV Agents - adverse effects
Anti-HIV Agents - chemical synthesis
Anti-HIV Agents - pharmacology
Biological Availability
Brain - drug effects
Cation Transport Proteins - drug effects
CCR5 Receptor Antagonists
Digestive System - drug effects
Ether-A-Go-Go Potassium Channels
HIV-1 - drug effects
HIV-1 - isolation & purification
Humans
In Vitro Techniques
Leukocytes, Mononuclear - drug effects
Leukocytes, Mononuclear - virology
Macaca fascicularis
Piperazines - adverse effects
Piperazines - chemical synthesis
Piperazines - chemistry
Piperazines - pharmacology
Piperidines - chemical synthesis
Piperidines - chemistry
Piperidines - pharmacology
Potassium Channels - drug effects
Potassium Channels, Voltage-Gated
Pyrimidines - adverse effects
Pyrimidines - chemical synthesis
Pyrimidines - chemistry
Pyrimidines - pharmacology
Rats
Stereoisomerism
Structure-Activity Relationship
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Summary:The nature and the size of the benzylic substituent are shown to be the key to controlling receptor selectivity (CCR5 vs M1, M2) and potency in the title compounds. Optimization of the lead benzylic methyl compound 3 led to the methoxymethyl analogue 30, which had excellent receptor selectivity and oral bioavailability in rats and monkeys. Compound 30 (Sch-417690/Sch-D), a potent inhibitor of HIV-1 entry into target cells, is currently in clinical trials.
ISSN:0022-2623