Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
J Med Chem. 2010 Mar 25;53(6):2443-63. doi: 10.1021/jm9015526.
A new class of HCV NS3/4a protease inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the P2 to P4 linker, and the P1 side chain of this class of compounds via a modular synthetic strategy allowed for the optimization of enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 35b (vaniprevir, MK-7009), which is active against both the genotype 1 and genotype 2 NS3/4a protease enzymes and has good plasma exposure and excellent liver exposure in multiple species.
设计了一类新型的 HCV NS3/4a 蛋白酶抑制剂，该抑制剂包含 P2 到 P4 位的大环约束。采用基于分子模型的策略，对 P2 杂环区域、P2 到 P4 键以及此类化合物的 P1 侧链进行了探索，通过模块化合成策略对酶活性、细胞活性以及口服给药后的大鼠肝脏暴露情况进行了优化。这些研究确定了临床候选药物 35b（凡奈普韦，MK-7009），它对基因型 1 和基因型 2 的 NS3/4a 蛋白酶均有活性，在多种物种中具有良好的血浆暴露量和优异的肝脏暴露量。
