Rudd Michael T, Butcher John W, Nguyen Kevin T, McIntyre Charles J, Romano Joseph J, Gilbert Kevin F, Bush Kimberly J, Liverton Nigel J, Holloway M Katharine, Harper Steven, Ferrara Marco, DiFilippo Marcello, Summa Vincenzo, Swestock John, Fritzen Jeff, Carroll Steven S, Burlein Christine, DiMuzio Jillian M, Gates Adam, Graham Donald J, Huang Qian, McClain Stephanie, McHale Carolyn, Stahlhut Mark W, Black Stuart, Chase Robert, Soriano Aileen, Fandozzi Christine M, Taylor Anne, Trainor Nicole, Olsen David B, Coleman Paul J, Ludmerer Steven W, McCauley John A
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA (USA).
ChemMedChem. 2015 Apr;10(4):727-35. doi: 10.1002/cmdc.201402558. Epub 2015 Mar 10.
With the goal of identifying inhibitors of hepatitis C virus (HCV) NS3/4a protease that are potent against a wide range of genotypes and clinically relevant mutant viruses, several subseries of macrocycles were investigated based on observations made during the discovery of MK-5172. Quinazolinone-containing macrocycles were identified as promising leads, and optimization for superior cross-genotype and mutant enzyme potency as well as rat liver and plasma concentrations following oral dosing, led to the development of MK-2748. Additional investigation of a series of bis-macrocycles containing a fused 18- and 15-membered ring system were also optimized for the same properties, leading to the discovery of MK-6325. Both compounds display the broad genotype and mutant potency necessary for clinical development as next-generation HCV NS3/4a protease inhibitors.
为了鉴定对多种基因型和临床相关突变病毒有效的丙型肝炎病毒（HCV）NS3/4a蛋白酶抑制剂，基于在MK-5172发现过程中的观察结果，对几个大环化合物子系列进行了研究。含喹唑啉酮的大环化合物被确定为有前景的先导化合物，通过优化以提高跨基因型和突变酶活性以及口服给药后的大鼠肝脏和血浆浓度，开发出了MK-2748。对一系列含有稠合的18元和15元环系统的双大环化合物也进行了同样性质的优化研究，从而发现了MK-6325。这两种化合物都具有作为下一代HCV NS3/4a蛋白酶抑制剂进行临床开发所需的广泛基因型和突变活性。
