Palani Anandan, Shapiro Sherry, Josien Hubert, Bara Thomas, Clader John W, Greenlee William J, Cox Kathleen, Strizki Julie M, Baroudy Bahige M
Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
J Med Chem. 2002 Jul 4;45(14):3143-60. doi: 10.1021/jm0200815.
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-CF(3), 4-OCF(3), 4-SO(2)Me, and 4-Cl) at the phenyl group are well-tolerated, and small alkyl substitutions (Me, Et, (n)()Pr, (i)()Pr, 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.
我们之前报道了4-[(Z)-(4-溴苯基)(乙氧基亚氨基)甲基]-1'-[(2,4-二甲基-3-吡啶基)羰基]-4'-甲基-1,4'-联哌啶N-氧化物1（SCH 351125）的发现，它是一种口服生物可利用的人CCR5拮抗剂，用于治疗HIV-1感染。在此，我们详细描述了从最初的先导化合物发现1的过程，以及针对肟基-哌啶基-哌啶系列中苯基、肟基和右侧酰胺基团取代优化的合成和构效关系研究。苯基上的取代基（4-溴、4-三氟甲基、4-三氟甲氧基、4-甲磺酰基和4-氯）耐受性良好，肟部分的小烷基取代基（甲基、乙基、正丙基、异丙基和环丙基甲基）对CCR5拮抗作用更有利。2,6-二甲基烟酰胺N-氧化物部分是右侧的最佳选择。该系列中的几种化合物，包括化合物1，在体外表现出优异的抗病毒活性。化合物1在啮齿动物和灵长类动物中具有良好的药代动力学特征、优异的口服生物利用度以及对多种原发性HIV-1分离株的强效抗病毒活性，是治疗HIV-1感染的一个潜在有前景的新候选药物。
