Discovery of ABT-267, a pan-genotypic inhibitor of HCV NS5A

  • J Med Chem. 2014 Mar 13;57(5):2047-57. doi: 10.1021/jm401398x.
David A DeGoey  1 ,  John T Randolph ,  Dachun Liu ,  John Pratt ,  Charles Hutchins ,  Pamela Donner ,  A Chris Krueger ,  Mark Matulenko ,  Sachin Patel ,  Christopher E Motter ,  Lissa Nelson ,  Ryan Keddy ,  Michael Tufano ,  Daniel D Caspi ,  Preethi Krishnan ,  Neeta Mistry ,  Gennadiy Koev ,  Thomas J Reisch ,  Rubina Mondal ,  Tami Pilot-Matias ,  Yi Gao ,  David W A Beno ,  Clarence J Maring ,  Akhter Molla ,  Emily Dumas ,  Andrew Campbell ,  Laura Williams ,  Christine Collins ,  Rolf Wagner ,  Warren M Kati
Affiliations
  • 1. Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States.
PMID: 24400777 DOI: 10.1021/jm401398x
Abstract

We describe here N-phenylpyrrolidine-based inhibitors of HCV NS5A with excellent potency, metabolic stability, and pharmacokinetics. Compounds with 2S,5S stereochemistry at the pyrrolidine ring provided improved genotype 1 (GT1) potency compared to the 2R,5R analogues. Furthermore, the attachment of substituents at the 4-position of the central N-phenyl group resulted in compounds with improved potency. Substitution with tert-butyl, as in compound 38 (ABT-267), provided compounds with low-picomolar EC50 values and superior pharmacokinetics. It was discovered that compound 38 was a pan-genotypic HCV Inhibitor, with an EC50 range of 1.7-19.3 pM against GT1a, -1b, -2a, -2b, -3a, -4a, and -5a and 366 pM against GT6a. Compound 38 decreased HCV RNA up to 3.10 log10 IU/mL during 3-day monotherapy in treatment-naive HCV GT1-infected subjects and is currently in phase 3 clinical trials in combination with an NS3 protease inhibitor with ritonavir (r) (ABT-450/r) and an NS5B non-nucleoside polymerase inhibitor (ABT-333), with and without ribavirin.

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