2. Academic Validation
  3. Discovery of MK-1220: A Macrocyclic Inhibitor of Hepatitis C Virus NS3/4A Protease with Improved Preclinical Plasma Exposure

Discovery of MK-1220: A Macrocyclic Inhibitor of Hepatitis C Virus NS3/4A Protease with Improved Preclinical Plasma Exposure

  • ACS Med Chem Lett. 2011 Jan 12;2(3):207-12. doi: 10.1021/ml1002426.
Michael T Rudd 1,  John A McCauley 1,  John W Butcher 1,  Joseph J Romano 1,  Charles J McIntyre 1,  Kevin T Nguyen 1,  Kevin F Gilbert 1,  Kimberly J Bush 1,  M Katharine Holloway 1,  John Swestock 1,  Bang-Lin Wan 1,  Steven S Carroll 1,  Jillian M DiMuzio 1,  Donald J Graham 1,  Steven W Ludmerer 1,  Mark W Stahlhut 1,  Christine M Fandozzi 1,  Nicole Trainor 1,  David B Olsen 1,  Joseph P Vacca 1,  Nigel J Liverton 1
Affiliations

Affiliation

  • 1 Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
PMID: 24900304 DOI: 10.1021/ml1002426
Abstract

The discovery of MK-1220 is reported along with the development of a series of HCV NS3/4A Protease Inhibitors containing a P2 to P4 macrocyclic constraint with improved preclinical pharmacokinetics. Optimization of the P2 heterocycle substitution pattern as well as the P3 amino acid led to compounds with greatly improved plasma exposure following oral dosing in both rats and dogs while maintaining excellent enzyme potency and cellular activity. These studies led to the identification of MK-1220.

Keywords

HCV; Hepatitis C; NS3/4A; macrocycle; ring-closing metathesis.

Figures
Products