Di Francesco M Emilia, Dessole Gabriella, Nizi Emanuela, Pace Paola, Koch Uwe, Fiore Fabrizio, Pesci Silvia, Di Muzio Jillian, Monteagudo Edith, Rowley Michael, Summa Vincenzo
Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.p.A., Merck Research Laboratories Rome, Via Pontina Km 30,600, 00040 Pomezia, Italy.
J Med Chem. 2009 Nov 26;52(22):7014-28. doi: 10.1021/jm900524b.
Our laboratories recently reported the discovery of P2-P4 macrocyclic inhibitors of HCV NS3/4A protease, characterized by high levels of potency and liver exposure. Within this novel class of inhibitors, we here describe the identification of a structurally diverse series of compounds featuring a 2-amino-1,3-thiazole as replacement of the carbamate in P4. Optimization studies focused on structural modifications in the P3, P2, and P1 regions of the macrocycle as well as on the linker chain and resulted in the discovery of several analogues characterized by excellent levels of enzyme and cellular activity. Among these, compound 59 displayed an attractive pharmacokinetic profile in preclinical species and showed sustained liver levels following oral administration in rats.
我们实验室最近报道了丙型肝炎病毒NS3/4A蛋白酶的P2 - P4大环抑制剂的发现，其特点是具有高活性水平和肝脏暴露量。在这一新型抑制剂类别中，我们在此描述了一系列结构多样的化合物的鉴定，这些化合物以2 - 氨基 - 1,3 - 噻唑取代P4中的氨基甲酸酯。优化研究集中在大环的P3、P2和P1区域以及连接链的结构修饰上，结果发现了几种具有优异酶活性和细胞活性水平的类似物。其中，化合物59在临床前物种中显示出有吸引力的药代动力学特征，并且在大鼠口服给药后肝脏水平持续存在。
