BMS-A78277 (1) is a 5,10-dihydrobenzo[beta][1,8]naphthyridine-N-oxide compound that resides in a class of novel non-nucleoside reverse transcriptase inhibitors (NNRTIs), displaying improved activity against clinically relevant mutants of HIV-1 and possessing pharmacokinetic profiles amenable to once-daily dosing. In the course of investigating the nonclinical metabolism of 1, a circulating metabolite specific to the cynomolgus monkey was identified and subsequently characterized as the carboxyindole metabolite 2. The present investigation describes the biotransformation of this NNRTI in cynomolgus monkey, one which results in a net ring contraction of 1. The use of mass spectrometry and high field NMR analysis aided in the structural characterization of metabolite 2, the source of which originated from the urine and bile of cynomolgus monkeys receiving oral doses of 1. Preparation of a synthetic standard of 2 not only provided ultimate structural confirmation but also afforded ample material for biological testing. The metabolism of 1 was investigated in monkey hepatocytes and hepatic subcellular fractions. While microsomes were incapable of generating metabolite 2, incubation of 1 in monkey S9 fractions as well as hepatocytes resulted in measurable levels of the carboxyindole metabolite. Consequently, incubation of 1 in monkey hepatocytes, which were suspended in media containing (18)O-labeled water, resulted in the incorporation of (18)O into the carboxyindole metabolite, 2. These data implicate a mechanism involving the bioactivation of 1 to an electrophilic intermediate that upon hydrolysis undergoes a concerted ring contraction, resulting in the formation of 2. Previously confined to discussions regarding the metabolism of natural products and select aliphatic heterocycles, the present investigation extends the discussion of metabolism-mediated ring contraction to aromatics such as the present naphthyridine compound, 1.

译文

BMS-A78277 (1) 是5,10-二氢苯并 [β][1,8] 萘啶-N-氧化物化合物,其位于一类新型非核苷类逆转录酶抑制剂 (NNRTIs) 中,显示出针对临床相关HIV-1突变体的改进活性,并具有适于每日一次给药的药代动力学特征。在研究1的非临床代谢的过程中,鉴定了食蟹猴特有的循环代谢物,并随后将其表征为羧酸吲哚代谢物2。本研究描述了这种NNRTI在食蟹猴中的生物转化,导致净环收缩为1。质谱和高场NMR分析的使用有助于代谢物2的结构表征,其来源来自食蟹猴的尿液和胆汁,口服剂量为1。合成标准2的制备不仅提供了最终的结构确认,而且为生物测试提供了充足的材料。在猴肝细胞和肝亚细胞级分中研究了1的代谢。虽然微粒体无法产生代谢物2,但在猴子S9级分和肝细胞中孵育1会导致可测量的羧酸吲哚代谢物水平。因此,将1悬浮在含有 (18)O标记的水的培养基中,在猴肝细胞中孵育,导致 (18)O掺入羧基吲哚代谢物2中。这些数据暗示了一种机制,该机制涉及1对亲电中间体的生物活化,该中间体在水解后会经历协同的环收缩,从而形成2。以前仅限于有关天然产物和某些脂肪族杂环的代谢的讨论,本研究将代谢介导的环收缩的讨论扩展到芳烃,例如本萘啶化合物1。

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