Details

Autor(en) / Beteiligte

• DeGoey, David A.
• Randolph, John T.
• Liu, Dachun
• Pratt, John
• Hutchins, Charles
• Donner, Pamela
• Krueger, A. Chris
• Matulenko, Mark
• Patel, Sachin
• Motter, Christopher E.
• Nelson, Lissa
• Keddy, Ryan
• Tufano, Michael
• Caspi, Daniel D.
• Krishnan, Preethi
• Mistry, Neeta
• Koev, Gennadiy
• Reisch, Thomas J.
• Mondal, Rubina
• Pilot-Matias, Tami
• Gao, Yi
• Beno, David W. A.
• Maring, Clarence J.
• Molla, Akhter
• Dumas, Emily
• Campbell, Andrew
• Williams, Laura
• Collins, Christine
• Wagner, Rolf
• Kati, Warren M.

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2014-03, Vol.57 (5), p.2047-2057

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.