Piperazine-Based CCR5 Antagonists as HIV-1 Inhibitors. II. Discovery of 1-[(2,4-Dimethyl-3-pyridinyl)carbonyl]-4- methyl-4-[3(S)-methyl-4-[1(S)-[4-(trifluoro- methyl)phenyl]ethyl]-1-piperazinyl]- piperidine N1-Oxide (Sch-350634), an Orally Bioavailable, Potent CCR5 Antagonist

作者： Jayaram R. Tagat , Ruo W. Steensma , Stuart W. McCombie , Dennis V. Nazareno , Sue-Ing Lin

关键词: Chemistry 、 Muscarinic acetylcholine receptor 、 Piperazine 、 CCR5 receptor antagonist 、 Stereochemistry 、 Structure–activity relationship 、 Antagonist 、 Bioavailability 、 Piperidine 、 Chemical synthesis

摘要: Truncation of the original piperidino-2(S)-methyl piperazine lead structure 2, from a family muscarinic antagonists, gave compound 8 which has improved selectivity for HIV-1 co-receptor CCR5 over receptors. Further optimization pharmacokinetic properties afforded Sch-350634 (1), prototypical piperazine-based antagonist, is potent inhibitor entry and replication in PBMCs. The title (1) excellent oral bioavailability rat, dog, monkey.

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Piperazine-Based CCR5 Antagonists as HIV-1 Inhibitors. II. Discovery of 1-[(2,4-Dimethyl-3-pyridinyl)carbonyl]-4- methyl-4-[3(S)-methyl-4-[1(S)-[4-(trifluoro- methyl)phenyl]ethyl]-1-piperazinyl]- piperidine N1-Oxide (Sch-350634), an Orally Bioavailable, Potent CCR5 Antagonist

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Piperazine-Based CCR5 Antagonists as HIV-1 Inhibitors. II. Discovery of 1-[(2,4-Dimethyl-3-pyridinyl)carbonyl]-4- methyl-4-[3(S)-methyl-4-[1(S)-[4-(trifluoro- methyl)phenyl]ethyl]-1-piperazinyl]- piperidine N1-Oxide (Sch-350634), an Orally Bioavailable, Potent CCR5 Antagonist

来源期刊

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