Discovery Chemistry, ViiV Healthcare, Branford, Connecticut 06405, United States.
Discovery Biology, ViiV Healthcare, Branford, Connecticut 06405, United States.
J Med Chem. 2023 Feb 9;66(3):1941-1954. doi: 10.1021/acs.jmedchem.2c01732. Epub 2023 Jan 31.
Long-acting (LA) human immunodeficiency virus-1 (HIV-1) antiretroviral therapy characterized by a ≥1 month dosing interval offers significant advantages over daily oral therapy. However, the criteria for compounds that enter clinical development are high. Exceptional potency and low plasma clearance are required to meet dose size requirements; excellent chemical stability and/or crystalline form stability is required to meet formulation requirements, and new antivirals in HIV-1 therapy need to be largely free of side effects and drug-drug interactions. In view of these challenges, the discovery that capsid inhibitors comprising a quinazolinone core tolerate a wide range of structural modifications while maintaining picomolar potency against HIV-1 infection , are assembled efficiently in a multi-component reaction, and can be isolated in a stereochemically pure form is reported herein. The detailed characterization of a prototypical compound, GSK878, is presented, including an X-ray co-crystal structure and subcutaneous and intramuscular pharmacokinetic data in rats and dogs.
长效（LA）人类免疫缺陷病毒-1（HIV-1）抗逆转录病毒疗法的特点是给药间隔≥1 个月，与每日口服治疗相比具有显著优势。然而，进入临床开发的化合物的标准很高。为了满足剂量要求，需要具有极高的效力和低血浆清除率；为了满足制剂要求，需要具有极好的化学稳定性和/或晶体形式稳定性，并且 HIV-1 治疗中的新抗病毒药物需要在很大程度上没有副作用和药物相互作用。鉴于这些挑战，人们发现包含喹唑啉酮核心的衣壳抑制剂在保持对 HIV-1 感染的皮摩尔效力的同时，能够容忍广泛的结构修饰，可以通过多组分反应高效组装，并可以以立体化学纯的形式分离。本文报道了衣壳抑制剂的详细特征，包括一个原型化合物 GSK878 的 X 射线共晶结构和在大鼠和狗中的皮下和肌肉内药代动力学数据。
