What question did this study set out to answer?

To design and optimize a novel macrocyclic class of HCV NS3/4a protease inhibitors with broad genotypic coverage, resistance-mutation coverage, and favorable liver distribution.

March 2, 2012ACS Medicinal Chemistry LettersOpen Access

Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor

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Authors

SHSteven J. HarperNorth Bristol NHS Trust JMJohn A. McCauleyUnited States Military Academy MRMichael T. RuddMerck & Co., Inc., Rahway, NJ, USA (United States)

Discussion

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Implication

Preclinical evaluation reveals broad antiviral efficacy and high liver exposure for the protease inhibitor MK-5172, suggesting potent pan-genotypic therapy against hepatitis C virus.

Key Points

To design and optimize a novel macrocyclic class of HCV NS3/4a protease inhibitors with broad genotypic coverage, resistance-mutation coverage, and favorable liver distribution.
Designed a P2-to-P4 macrocyclic constraint scaffold guided by molecular modeling of HCV NS3/4a protease.
Optimized the P2 and linker regions to enhance enzyme potency, cellular activity, and in vivo pharmacokinetics.
Evaluated oral bioavailability, plasma exposure, and liver tissue exposure across preclinical animal models, including rats.
Identified MK-5172 (compound 15), a candidate demonstrating potent inhibition against HCV genotypes 1, 2, and 3 NS3/4a enzymes.
Achieved robust cellular antiviral activity against major clinically relevant drug-resistant mutant enzymes.
Demonstrated favorable plasma pharmacokinetics and high liver exposure following oral dosing across multiple animal species.

Cite This Study

Harper et al. (2012) studied this question.

synapsesocial.com/papers/6a7ca0f5f108d7d7faba495e https://doi.org/10.1021/ml300017p

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Implication

Preclinical evaluation reveals broad antiviral efficacy and high liver exposure for the protease inhibitor MK-5172, suggesting potent pan-genotypic therapy against hepatitis C virus.

Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor

Discussion

Member takes

Implication

Key Points

Cite This Study

Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor

Discussion

Member takes

Implication

Key Points

Cite This Study

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