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

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DeGoey DA, Randolph JT, Liu D, Pratt J, Hutchins C, Donner P, Krueger AC, Matulenko M, Patel S, Motter CE, Nelson L, Keddy R, Tufano M, Caspi DD, Krishnan P, Mistry N, Koev G, Reisch TJ, Mondal R, Pilot-Matias T, Gao Y, Beno DW, Maring CJ, Molla A, Dumas E, Campbell A, Williams L, Collins C, Wagner R, Kati WM

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. Epub 2014 Jan 15.

PubMed ID

24400777 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drugs

Ombitasvir

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Ombitasvir	Nonstructural protein 5A	Protein	Hepatitis C Virus	Yes	Inhibitor	Details