Synthesis, SAR, and Biological Evaluation of Oximino-Piperidino-Piperidine Amides. 1. Orally Bioavailable CCR5 Receptor Antagonists with Potent Anti-HIV Activity

Autor: Palani, A., Shapiro, S., Josien, H., Bara, T., Clader, J. W., Greenlee, W. J., Cox, K., Strizki, J. M., Baroudy, B. M.
Zdroj: Journal of Medicinal Chemistry; July 2002, Vol. 45 Issue: 14 p3143-3160, 18p
Abstrakt: We previously reported the discovery of 4-[(Z)-(4-bromophenyl)(ethoxyimino)methyl]-1‘-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4‘-methyl-1,4‘-bipiperidine N-oxide 1 (SCH 351125) as an orally bioavailable human CCR5 antagonist for the treatment of HIV-1 infection. Herein, we describe in detail the discovery of 1 from our initial lead compound as well as the synthesis and SAR studies directed toward optimization of substitution at the phenyl, oxime, and right-hand side amide groups in the oximino-piperidino-piperidine series. Substitutions (4-Br, 4-CF3, 4-OCF3, 4-SO2Me, and 4-Cl) at the phenyl group are well-tolerated, and small alkyl substitutions (Me, Et, nPr, iPr, and cyclopropyl methyl) at the oxime moiety are preferred for CCR5 antagonism. The 2,6-dimethylnicotinamide N-oxide moiety is the optimal choice for the right-hand side. Several compounds in this series, including compound 1, exhibited excellent antiviral activity in vitro. Compound 1, which has a favorable pharmacokinetic profile in rodents and primates, excellent oral bioavailability, and potent antiviral activity against a wide range of primary HIV-1 isolates, is a potentially promising new candidate for treatment of HIV-1 infection.
Databáze: Supplemental Index