Rational Design, Synthesis, and Structure–Activity Relationship of a Novel Isoquinolinone-Based Series of HBV Capsid Assembly Modulators Leading to the Identification of Clinical Candidate AB-836,Journal of Medicinal Chemistry

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Rational Design, Synthesis, and Structure–Activity Relationship of a Novel Isoquinolinone-Based Series of HBV Capsid Assembly Modulators Leading to the Identification of Clinical Candidate AB-836
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-04 , DOI: 10.1021/acs.jmedchem.4c01568
Andrew G Cole ₁ , Steven G Kultgen ₁ , Nagraj Mani ₁ , Kristi Yi Fan ₁ , Andrzej Ardzinski ₁ , Kim Stever ₁ , Bruce D Dorsey ₁ , Eugen F Mesaros ₁ , Emily P Thi ₁ , Ingrid Graves ₁ , Sunny Tang ₁ , Troy O Harasym ₁ , Amy C H Lee ₁ , Andrea Olland ₂ , Robert K Suto ₂ , Michael J Sofia ₁

Affiliation

Inhibition of Hepatitis B Virus (HBV) replication by small molecules that modulate capsid assembly and the encapsidation of pgRNA and viral polymerase by HBV core protein is a clinically validated approach toward the development of new antivirals. Through definition of a minimal pharmacophore, a series of isoquinolinone-based capsid assembly modulators (CAMs) was identified. Structural biology analysis revealed that lead molecules possess a unique binding mode, exploiting electrostatic interactions with accessible phenylalanine and tyrosine residues. Key analogs demonstrated excellent primary potency, absorption, distribution, metabolism, and excretion (ADME) and pharmacokinetic properties, and efficacy in a mouse model of HBV. The optimized lead also displayed potent inhibition of capsid uncoating in HBV-infected HepG2 cells expressing the sodium-taurocholate cotransporting polypeptide (NTCP) receptor, affecting the generation of HBsAg and cccDNA establishment. Based on these results, isoquinolinone derivative AB-836 was advanced into clinical development. In Phase 1b trials, AB-836 demonstrated >3 log₁₀ reduction in serum HBV DNA, however, further development was discontinued due to the observation of incidental alanine aminotransferase (ALT) elevations.

中文翻译：

基于异喹啉酮的新型 HBV 衣壳组装调节剂系列的合理设计、合成和构效关系导致临床候选药物 AB-836 的鉴定

调节衣壳组装的小分子抑制乙型肝炎病毒（HBV）复制以及 HBV 核心蛋白对 pgRNA 和病毒聚合酶的包封是开发新型抗病毒药物的一种经过临床验证的方法。通过定义最小药效团，确定了一系列基于异喹啉酮的衣壳组装调节剂（CAMs）。结构生物学分析表明，先导分子具有独特的结合模式，利用与可接近的苯丙氨酸和酪氨酸残基的静电相互作用。关键类似物在 HBV 小鼠模型中表现出优异的初级效价、吸收、分布、代谢和排泄（ADME）和药代动力学特性以及疗效。优化的导线还显示出对表达钠-牛磺胆酸共转运多肽（NTCP）受体的 HBV 感染的 HepG2 细胞中衣壳脱壳的有效抑制，从而影响 HBsAg 的产生和 cccDNA 的建立。基于这些结果，异喹啉酮衍生物 AB-836 进入临床开发阶段。在 1b 期试验中，AB-836 显示血清 HBV DNA 的 >3 log₁₀ 降低，然而，由于观察到偶然的丙氨酸氨基转移酶（ALT）升高，进一步开发停止。

更新日期：2024-09-04

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