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

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journal contribution
posted on 2016-01-14, 00:00 authored by Santhosh F. Neelamkavil, Sony Agrawal, Thomas Bara, Chad Bennett, Sathesh Bhat, Dipshikha Biswas, Linda Brockunier, Nicole Buist, Duane Burnette, Mark Cartwright, Samuel Chackalamannil, Robert Chase, Mariappan Chelliah, Austin Chen, Martin Clasby, Vincent J. Colandrea, Ian W. Davies, Keith Eagen, Zhuyan Guo, Yongxin Han, John Howe, Charles Jayne, Hubert Josien, Stacia Kargman, Karen Marcantonio, Shouwu Miao, Randy Miller, Andrew Nolting, Patrick Pinto, Murali Rajagopalan, Rebecca T. Ruck, Unmesh Shah, Aileen Soriano, Donald Sperbeck, Francisco Velazquez, Jin Wu, Yan Xia, Srikanth Venkatraman
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.