3tyq

Publication Abstract from PubMed

Starting from indole-based C-3 pyridone HCV NS5B polymerase inhibitor 2, structure-activity relationship (SAR) investigations of the indole N-1 benzyl moiety were performed. This study led to the discovery of irreversible inhibitors with para-fluoro-sulfone- or para-fluoro-nitro-substituted N-1 benzyl groups which achieved breakthrough replicon assay potency (EC50 = 1 nM). The formation of a covalent bond with adjacent cysteine-366 thiol was was proved by mass spectroscopy and X-ray crystal structure studies. The C-5 SAR investigation demonstrated that small alkyl groups were preferred. The C-5 ethyl C-2 carboxylic acid derivative 47 had an excellent oral area-under-the-curve (AUC) of 18 muM.h (10 mg/kg). Its oral exposure in monkeys and dogs was also very good. The NMR ALARM assay, mass spectroscopy experiments, in vitro counter screening and toxicology assays demonstrated that the covalent bond formation between compound 47 and the protein was highly selective and specific. The overall excellent profile of 47 made it an interesting candidate for further investigation.

A Novel Class of Highly Potent Irreversible Hepatitis C Virus (HCV) NS5B Polymerase Inhibitors.,Chen KX, Lesburg CA, Vibulbhan B, Yang W, Chan TY, Venkatraman S, Velazquez F, Zeng Q, Bennett F, Anilkumar GN, Duca J, Jiang Y, Pinto P, Wang L, Huang Y, Selyutin O, Gavalas S, Pu H, Agrawal S, Feld B, Huang HC, Li C, Cheng KC, Shih NY, Kozlowski JA, Rosenblum SB, Njoroge FG J Med Chem. 2012 Jan 16. PMID:22247956^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.