Discovery of ABT-267, a Pan-Genotypic Inhibitor of HCV NS5A

被引：112

作者：

DeGoey, David A. ^{[1
]}

Randolph, John T. ^{[1
]}

Liu, Dachun ^{[1
]}

Pratt, John ^{[1
]}

Hutchins, Charles ^{[1
]}

Donner, Pamela ^{[1
]}

Krueger, A. Chris ^{[1
]}

Matulenko, Mark ^{[1
]}

Patel, Sachin ^{[1
]}

Motter, Christopher E. ^{[1
]}

Nelson, Lissa ^{[1
]}

Keddy, Ryan ^{[1
]}

Tufano, Michael ^{[1
]}

Caspi, Daniel D. ^{[1
]}

Krishnan, Preethi ^{[1
]}

Mistry, Neeta ^{[1
]}

Koev, Gennadiy ^{[1
]}

Reisch, Thomas J. ^{[1
]}

Mondal, Rubina ^{[1
]}

Pilot-Matias, Tami ^{[1
]}

Gao, Yi ^{[1
]}

Beno, David W. A. ^{[1
]}

Maring, Clarence J. ^{[1
]}

Molla, Akhter ^{[1
]}

Dumas, Emily ^{[1
]}

Campbell, Andrew ^{[1
]}

Williams, Laura ^{[1
]}

Collins, Christine ^{[1
]}

Wagner, Rolf ^{[1
]}

Kati, Warren M. ^{[1
]}

机构：

[1] AbbVie Inc, Res & Dev, N Chicago, IL 60064 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 05期

关键词：

HUMAN-IMMUNODEFICIENCY-VIRUS; CHRONIC HEPATITIS-C; ACTING ANTIVIRAL AGENTS; PLASMA-PROTEIN BINDING; IN-VITRO; POTENT; REPLICATION; COMBINATION; RESISTANCE; MUTATIONS;

D O I：

10.1021/jm401398x

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 log(10) 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.

引用

页码：2047 / 2057

页数：11

共 33 条

[1]

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