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Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor.


ABSTRACT: We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.

SUBMITTER: Neelamkavil SF 

PROVIDER: S-EPMC4716590 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor.

Neelamkavil Santhosh F SF   Agrawal Sony S   Bara Thomas T   Bennett Chad C   Bhat Sathesh S   Biswas Dipshikha D   Brockunier Linda L   Buist Nicole N   Burnette Duane D   Cartwright Mark M   Chackalamannil Samuel S   Chase Robert R   Chelliah Mariappan M   Chen Austin A   Clasby Martin M   Colandrea Vincent J VJ   Davies Ian W IW   Eagen Keith K   Guo Zhuyan Z   Han Yongxin Y   Howe John J   Jayne Charles C   Josien Hubert H   Kargman Stacia S   Marcantonio Karen K   Miao Shouwu S   Miller Randy R   Nolting Andrew A   Pinto Patrick P   Rajagopalan Murali M   Ruck Rebecca T RT   Shah Unmesh U   Soriano Aileen A   Sperbeck Donald D   Velazquez Francisco F   Wu Jin J   Xia Yan Y   Venkatraman Srikanth S  

ACS medicinal chemistry letters 20151222 1


We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimizat  ...[more]

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