1258232-48-2Relevant academic research and scientific papers
Discovery of ABT-267, a pan-genotypic inhibitor of HCV NS5A
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.
, p. 2047 - 2057 (2014/04/03)
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.
