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

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.

SUBMITTER: Rudd MT

PROVIDER: S-EPMC4017977 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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

Rudd Michael T MT McCauley John A JA Butcher John W JW Romano Joseph J JJ McIntyre Charles J CJ Nguyen Kevin T KT Gilbert Kevin F KF Bush Kimberly J KJ Holloway M Katharine MK Swestock John J Wan Bang-Lin BL Carroll Steven S SS DiMuzio Jillian M JM Graham Donald J DJ Ludmerer Steven W SW Stahlhut Mark W MW Fandozzi Christine M CM Trainor Nicole N Olsen David B DB Vacca Joseph P JP Liverton Nigel J NJ

ACS medicinal chemistry letters 20110112 3

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. ...[more]

PMID: 24900304

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