2. Academic Validation
  3. 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

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

Affiliation

  • 1 Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA (USA). michael_rudd@merck.com.
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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