P2-quinazolinones and bis-macrocycles as new templates for next-generation hepatitis C virus NS3/4a protease inhibitors: discovery of MK-2748 and MK-6325

  • ChemMedChem. 2015 Apr;10(4):727-35. doi: 10.1002/cmdc.201402558.
Michael T Rudd  1 ,  John W Butcher ,  Kevin T Nguyen ,  Charles J McIntyre ,  Joseph J Romano ,  Kevin F Gilbert ,  Kimberly J Bush ,  Nigel J Liverton ,  M Katharine Holloway ,  Steven Harper ,  Marco Ferrara ,  Marcello DiFilippo ,  Vincenzo Summa ,  John Swestock ,  Jeff Fritzen ,  Steven S Carroll ,  Christine Burlein ,  Jillian M DiMuzio ,  Adam Gates ,  Donald J Graham ,  Qian Huang ,  Stephanie McClain ,  Carolyn McHale ,  Mark W Stahlhut ,  Stuart Black ,  Robert Chase ,  Aileen Soriano ,  Christine M Fandozzi ,  Anne Taylor ,  Nicole Trainor ,  David B Olsen ,  Paul J Coleman ,  Steven W Ludmerer ,  John A McCauley
Affiliations
  • 1. Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA (USA). [email protected].
PMID: 25759009 DOI: 10.1002/cmdc.201402558
Abstract

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.

Keywords
MK-2748; MK-6325; antiviral agents; hepatitis C; macrocycles.
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