Delving into the Latest Updates on MK-8831 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

Mechanism

NS3 inhibitors(Hepatitis C virus (HCV) nonstructural protein 3 inhibitors), NS3/NS4A inhibitors(Hepatitis C virus serine protease, NS3/NS4A inhibitors)

Therapeutic Areas

Infectious DiseasesDigestive System Disorders

Active Indication

Hepatitis C

Inactive Indication-

Originator Organization

Merck Research Laboratories Massachusetts LLC

Active Organization

Merck & Co., Inc.

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC40H50F3N5O9S

InChIKeyGBJKXZJNFVRHCK-XPTVTBSVSA-N

CAS Registry1565770-83-3

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

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.

100 Deals associated with MK-8831

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