J Med Chem. 2018 Jul 26;61(14):6308-6327. doi: 10.1021/acs.jmedchem.8b00759. Epub 2018 Jul 13.
The optimization of the 4-methoxy-6-azaindole series of HIV-1 attachment inhibitors (AIs) that originated with 1 to deliver temsavir (3, BMS-626529) is described. The most beneficial increases in potency and pharmacokinetic (PK) properties were attained by incorporating N-linked, sp-hybridized heteroaryl rings at the 7-position of the heterocyclic nucleus. Compounds that adhered to a coplanarity model afforded targeted antiviral potency, leading to the identification of 3 with characteristics that provided for targeted exposure and PK properties in three preclinical species. However, the physical properties of 3 limited plasma exposure at higher doses, both in preclinical studies and in clinical trials as the result of dissolution- and/or solubility-limited absorption, a deficiency addressed by the preparation of the phosphonooxymethyl prodrug 4 (BMS-663068, fostemsavir). An extended-release formulation of 4 is currently in phase III clinical trials where it has shown promise as part of a drug combination therapy in highly treatment-experienced HIV-1 infected patients.
本文描述了以 1 为起始物对 HIV-1 附着抑制剂（AIs）的 4-甲氧基-6-氮杂吲哚系列进行优化的过程。通过在杂环核的 7 位引入 N 连接的、sp 杂化的杂芳环，可以获得最有利的效力和药代动力学（PK）性质的提高。符合共面性模型的化合物提供了靶向抗病毒效力，从而确定了 3 的特性，为三种临床前物种提供了靶向暴露和 PK 特性。然而，3 的物理性质限制了在较高剂量下的血浆暴露，无论是在临床前研究还是临床试验中，这都是由于溶解和/或溶解度限制吸收所致，这一缺陷通过制备膦氧甲基前药 4（BMS-663068， fostemsavir）得到了解决。4 的缓释制剂目前正在进行 III 期临床试验，作为一种药物联合治疗方案的一部分，它在治疗经验丰富的 HIV-1 感染患者中显示出了良好的前景。
