Discovery of AIC263282, a Hepatitis B Virus Capsid Assembly Modulator Ready for Candidate Profiling

Hepatitis
B Virus (HBV) infections remain a threat to the global
public health. Nucleoside analogues remain the mainstay of therapy
despite their discouraging cure rates achieved. Capsid assembly modulators
(CAMs) have been at the center of HBV research, but despite having
shown clinical efficacy on viral load in clinical studies, market
entry has been elusive. Herein, we present the optimization program
of our lead series. Setting our focus on potency, solubility, and
hERG liability, these studies resulted in AIC263282, a new, potent
capsid assembly modulator with improved physicochemical properties,
which is ready for profiling as a preclinical candidate.

乙型肝炎病毒（Hepatitis B Virus, HBV）感染仍是全球公共卫生领域的重大威胁。尽管核苷类似物疗法的临床治愈率不尽如人意，但此类药物仍是当前乙肝治疗的主流方案。衣壳组装调节剂（Capsid Assembly Modulators, CAMs）一直是HBV研究的核心方向；尽管此类调节剂在临床研究中已展现出对病毒载量的临床疗效，但其成功获批上市仍困难重重。本文详述了本团队先导化合物系列的优化研发历程。本研究以活性、溶解性及hERG风险为核心优化目标，最终得到化合物AIC263282——一种全新的强效衣壳组装调节剂，其理化性质得到显著改善，可作为临床前候选化合物开展后续成药性评价工作。