2. Academic Validation
  3. Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis C virus NS3/4a protease inhibitor

Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis C virus NS3/4a protease inhibitor

  • J Med Chem. 2010 Mar 25;53(6):2443-63. doi: 10.1021/jm9015526.
John A McCauley 1,  Charles J McIntyre,  Michael T Rudd,  Kevin T Nguyen,  Joseph J Romano,  John W Butcher,  Kevin F Gilbert,  Kimberly J Bush,  M Katharine Holloway,  John Swestock,  Bang-Lin Wan,  Steven S Carroll,  Jillian M DiMuzio,  Donald J Graham,  Steven W Ludmerer,  Shi-Shan Mao,  Mark W Stahlhut,  Christine M Fandozzi,  Nicole Trainor,  David B Olsen,  Joseph P Vacca,  Nigel J Liverton
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. john_mccauley@merck.com
PMID: 20163176 DOI: 10.1021/jm9015526
Abstract

A new class of HCV NS3/4a Protease Inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the P2 to P4 linker, and the P1 side chain of this class of compounds via a modular synthetic strategy allowed for the optimization of Enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 35b (vaniprevir, MK-7009), which is active against both the genotype 1 and genotype 2 NS3/4a protease enzymes and has good plasma exposure and excellent liver exposure in multiple species.

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