Discovery of Narlaprevir (SCH 900518): A Potent, Second Generation HCV NS3 Serine Protease Inhibitor

  • ACS Med Chem Lett. 2010 Feb 15;1(2):64-9. doi: 10.1021/ml9000276.
Ashok Arasappan  1 ,  Frank Bennett  1 ,  Stephane L Bogen  1 ,  Srikanth Venkatraman  1 ,  Melissa Blackman  1 ,  Kevin X Chen  1 ,  Siska Hendrata  1 ,  Yuhua Huang  1 ,  Regina M Huelgas  1 ,  Latha Nair  1 ,  Angela I Padilla  1 ,  Weidong Pan  1 ,  Russell Pike  1 ,  Patrick Pinto  1 ,  Sumei Ruan  1 ,  Mousumi Sannigrahi  1 ,  Francisco Velazquez  1 ,  Bancha Vibulbhan  1 ,  Wanli Wu  1 ,  Weiying Yang  1 ,  Anil K Saksena  1 ,  Viyyoor Girijavallabhan  1 ,  Neng-Yang Shih  1 ,  Jianshe Kong  1 ,  Tao Meng  1 ,  Yan Jin  1 ,  Jesse Wong  1 ,  Paul McNamara  1 ,  Andrew Prongay  1 ,  Vincent Madison  1 ,  John J Piwinski  1 ,  Kuo-Chi Cheng  1 ,  Richard Morrison  1 ,  Bruce Malcolm  1 ,  Xiao Tong  1 ,  Robert Ralston  1 ,  F George Njoroge  1
Affiliations
  • 1. Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033.
PMID: 24900178 DOI: 10.1021/ml9000276
Abstract

Boceprevir (SCH 503034), 1, a novel HCV NS3 Serine Protease Inhibitor discovered in our laboratories, is currently undergoing phase III clinical trials. Detailed investigations toward a second generation protease inhibitor culminated in the discovery of narlaprevir (SCH 900518), 37, with improved potency (∼10-fold over 1), pharmacokinetic profile and physicochemical characteristics, currently in phase II human trials. Exploration of synthetic sequence for preparation of 37 resulted in a route that required no silica gel purification for the entire synthesis.

Keywords
Hepatitis C virus NS3 serine protease inhibitor; SCH 900518; narlaprevir; α-ketoamide.
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