The discovery of IDX21437: Design, synthesis and antiviral evaluation of 2'-α-chloro-2'-ß-C-methyl branched uridine pronucleotides as potent liver-targeted HCV polymerase inhibitors.

Herein we describe the discovery of IDX21437 35b, a novel RPd-aminoacid-based phosphoramidate prodrug of 2'-α-chloro-2'-ß-C-methyluridine monophosphate. Its corresponding triphosphate 6 is a potent inhibitor of the HCV NS5B RNA-dependent RNA polymerase (RdRp). Despite showing very weak activity in the in vitro Huh-7 cell based HCV replicon assay, 35b demonstrated high levels of active triphosphate 6 in mouse liver and human hepatocytes. A biochemical study revealed that the metabolism of 35b was mainly attributed to carboxyesterase 1 (CES1), an enzyme which is underexpressed in HCV Huh-7-derived replicon cells. Furthermore, due to its metabolic activation, 35b was efficiently processed in liver cells compared to other cell types, including human cardiomyocytes. The selected RP diastereoisomeric configuration of 35b was assigned by X-ray structural determination. 35b is currently in Phase II clinical trials for the treatment of HCV infection.

Synthesis of potent and broad genotypically active NS5B HCV non-nucleoside inhibitors binding to the thumb domain allosteric site 2 of the viral polymerase.

The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells and, as a consequence, is an attractive target for selective inhibition. This Letter describes the discovery of a new family of HCV NS5B non-nucleoside inhibitors, based on the bioisosterism between amide and phosphonamidate functions. As part of this program, SAR in this new series led to the identification of IDX17119, a potent non-nucleoside inhibitor, active on the genotypes 1b, 2a, 3a and 4a. The structure and binding domain of IDX17119 were confirmed by X-ray co-crystallization study.

HBV replication inhibitors.

Chronic Hepatitis B Virus infections afflict >250 million people and kill nearly 1 million annually. Current non-curative therapies are dominated by nucleos(t)ide analogs (NAs) that profoundly but incompletely suppress DNA synthesis by the viral reverse transcriptase. Residual HBV replication during NA therapy contributes to maintenance of the critical nuclear reservoir of the HBV genome, the covalently-closed circular DNA, and to ongoing infection of naive cells. Identification of next-generation NAs with improved efficacy and safety profiles, often through novel prodrug approaches, is the primary thrust of ongoing efforts to improve HBV replication inhibitors. Inhibitors of the HBV ribonuclease H, the other viral enzymatic activity essential for viral genomic replication, are in preclinical development. The complexity of HBV's reverse transcription pathway offers many other potential targets. HBV's protein-priming of reverse transcription has been briefly explored as a potential target, as have the host chaperones necessary for function of the HBV reverse transcriptase. Improved inhibitors of HBV reverse transcription would reduce HBV's replication-dependent persistence mechanisms and are therefore expected to become a backbone of future curative combination anti-HBV therapies.