By Ingallinella, Paolo; Peier, Andrea M.; Pocai, Alessandro; Di Marco, Annalise; Desai, Kunal; Zytko, Karolina;…
By Harper, Steven; McCauley, John A.; Rudd, Michael T.; Ferrara, Marco; DiFilippo, Marcello; Crescenzi, Benedetta; Koch, Uwe; Petrocchi, Alessia; Holloway, M. Katharine; Butcher, John W.; et al
From ACS Medicinal Chemistry Letters (2012), 3(4), 332-336. Language: English, Database: CAPLUS, DOI:10.1021/ml300017p
A new class of HCV NS3/4a protease inhibitors contg. a P2 to P4 macrocyclic constraint was designed using a mol. modeling-derived strategy. Building on the profile of previous clin. compds. and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clin. candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clin. relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.