设计和口服生物4-甲基基于Heteroaryldihydropyrimidine乙型肝炎病毒

StephenW

J Med Chem. 2016 Jul 26. [Epub ahead of print]
Design and Synthesis of Orally Bioavailable 4-Methyl Heteroaryldihydropyrimidine Based Hepatitis B Virus (HBV) Capsid Inhibitors.Qiu Z, Lin X, Zhou M, Liu Y, Zhu W, Chen W, Zhang W, Guo L, Liu H, Wu G, Huang M, Jiang M, Xu Z, Zhou ZJ, Qin N, Ren S, Qiu H, Zhong S, Zhang Y, Zhang Y, Wu X, Shi L, Shen F, Mao Y, Zhou X, Yang W, Wu JZ, Yang G, Mayweg AV, Shen HC, Tang G.
AbstractTargeting the capsid protein of hepatitis B virus (HBV) and thus interrupting normal capsid formation have been an attractive approach to block the replication of HBV viruses. We carried out multidimensional structural optimizations based on the heteroaryldihydropyrimidine (HAP) analogue Bay41-4109 (1) and identified a novel series of HBV capsid inhibitors that demonstrated promising cellular selectivity indexes, metabolic stabilities, and in vitro safety profiles. Herein we disclose the design, synthesis, structure-activity relationship (SAR), co-crystal structure in complex with HBV capsid proteins, and in vivo pharmacological study of the 4-methyl HAP analogues. In particular, the (2S, 4S)-4,4-difluoroproline substituted analogue 34a demonstrate high oral bioavailability and liver exposure, and achieve > 2 log viral load reduction in a hydrodynamic injected (HDI) HBV mouse model.


PMID:27458651DOI:10.1021/acs.jmedchem.6b00879

StephenW

J Med化学。 2016年七月26提前打印EPUB]
设计和口服生物4-甲基基于Heteroaryldihydropyrimidine乙型肝炎病毒（HBV）衣壳蛋白抑制剂的合成。
邱Z，林X，周男，刘毅，朱W，陈炜，张宽，郭L，刘H，吴G，黄呒，江男，徐Z，周ZJ，秦N，任S，邱^ h钟S，张艳，张Y，吴X，石L，沉楼茂，周X，杨W，吴JZ，杨G，Mayweg AV，沉HC，唐G.
抽象

定位乙型肝炎病毒（HBV）的衣壳蛋白，从而中断正常衣壳形成一直到方框的乙肝病毒的复制有吸引力的方法。我们进行了基于所述heteroaryldihydropyrimidine（HAP）类似物Bay41-4109多维结构优化（1），并确定一种新的一系列表现出有前途的蜂窝选择性索引，代谢稳定性，并在体外安全型材HBV衣壳抑制剂。这里，我们公开了设计，合成，结构 - 活性关系（SAR），共晶与HBV衣壳蛋白结构复杂，并且在体内4-甲基HAP类似物的药理研究。具体地，（2S，4S）-4,4- difluoroproline取代的类似物34A展示高口服生物利用率和肝脏暴露，并实现在一流体动力注射（HDI）的HBV小鼠模型> 2日志病毒载量下降。

结论：
    27458651
DOI：
    10.1021 / acs.jmedchem.6b00879