Details

Autor(en) / Beteiligte

• Belema, Makonen
• Nguyen, Van N.
• Romine, Jeffrey L.
• St. Laurent, Denis R.
• Lopez, Omar D.
• Goodrich, Jason T.
• Nower, Peter T.
• O’Boyle, Donald R.
• Lemm, Julie A.
• Fridell, Robert A.
• Gao, Min
• Fang, Hua
• Krause, Rudolph G.
• Wang, Ying-Kai
• Oliver, A. Jayne
• Good, Andrew C.
• Knipe, Jay O.
• Meanwell, Nicholas A.
• Snyder, Lawrence B.

Titel

Hepatitis C Virus NS5A Replication Complex Inhibitors. Part 6: Discovery of a Novel and Highly Potent Biarylimidazole Chemotype with Inhibitory Activity Toward Genotypes 1a and 1b Replicons

Ist Teil von

• Journal of medicinal chemistry, 2014-03, Vol.57 (5), p.1995-2012

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• A medicinal chemistry campaign that was conducted to address a potential genotoxic liability associated with an aniline-derived scaffold in a series of HCV NS5A inhibitors with dual GT-1a/-1b inhibitory activity is described. Anilides 3b and 3c were used as vehicles to explore structural modifications that retained antiviral potency while removing the potential for metabolism-based unmasking of the embedded aniline. This effort resulted in the discovery of a highly potent biarylimidazole chemotype that established a potency benchmark in replicon assays, particularly toward HCV GT-1a, a strain with significant clinical importance. Securing potent GT-1a activity in a chemotype class lacking overt structural liabilities was a critical milestone in the effort to realize the full clinical potential of targeting the HCV NS5A protein.