Discovery of a Novel Class of Potent HCV NS4B Inhibitors: SAR Studies on Piperazinone Derivatives

Abstract

HTS screening identified compound 2a (piperazinone derivative) as a low micromolar HCV genotype 1 (GT-1) inhibitor. Resistance mapping studies suggested that this piperazinone chemotype targets the HCV nonstructural protein NS4B. Extensive SAR studies were performed around 2a and the amide function and the C-3/C-6 cis stereochemistry of the piperazinone core were essential for HCV activity. A 10-fold increase in GT-1 potency was observed when the chiral phenylcyclopropyl amide side chain of 2a was replaced with p-fluorophenylisoxazole-carbonyl moiety (67). Replacing the C-6 nonpolar hydrophobic moiety of 67 with a phenyl moiety (95) did not diminish the GT-1 potency. A heterocyclic thiophene moiety (103) and an isoxazole moiety (108) were incorporated as isosteric replacements for the C-6 phenyl moiety (95), resulting in significant improvement in GT-1b and 1a potency. However, the piperazonone class of compounds lacks GT-2 activity and, consequently, were not pursued further into development.

Encoded Library Technology Screening of Hepatitis C Virus NS4B Yields a Small-Molecule Compound Series with In Vitro Replicon Activity

“…In addition, we determined the shift in potency against a genotype 2a chimera panel and looked at the effects of individual amino acid substitutions. Like reports from other series, the amino acid at position 98 was found to be a key determinant of potency (9,(12)(13)(14). This resides in the proposed first transmembrane region of NS4B (34).…”

“…Despite a fairly thorough chemistry effort (Ͼ200 compounds synthesized), we were unable to find compounds that were more potent than the ones described against HCV 1b or that had a relative improvement of potency against genotype 1a or 2a. Reports from other chemical series have shown a similar loss of potency against genotype 2a (6,8,9,13,14), although in the case of Phillips et al (14), while the potency against genotype 2a shifted about 30-fold compared with that against genotype 1b, it was still in the low nanomolar range.…”

“…Other classes of DAAs showing clinical efficacy target the NS5A protein (3,4) or viral polymerase (NS5B; reviewed in reference 5). Of the other viral proteins, several smallmolecule DAAs to nonstructural protein NS4B have been identified (6)(7)(8)(9)(10)(11)(12)(13)(14), but to date, there are no examples of clinically active NS4B-targeting compounds.…”

Asymmetric Epoxidation of Alkylidenemalononitriles: Key Step for One-Pot Approach to Enantioenriched 3-Substituted Piperazin-2-ones

“…A regioselective S N 2 ring-opening reaction of the enantioenriched gem-dicyano epoxides by 1,2-diamines, followed by an intramolecular attack of the other amine group to the in situ formed acyl cyanide intermediate, would lead to enantioenriched piperazin-2-ones. 14 Developing asymmetric syntheses of substituted piperazin-2-ones is highly desirable, given their relevance as pharmacophores showing a wide range of biological activities as HDAC inhibitors, 15 bradykinin receptor antagonists, 16 serotonin receptor antagonists, 17 hepatitis C virus replication inhibitors, 18 antihelminthics, 19 and antagonist GW597599, 20 to cite a few. Additionally, they play a central role in conformationally constrained peptides.…”

A Journey around the Medicinal Chemistry of Hepatitis C Virus Inhibitors Targeting NS4B: From Target to Preclinical Drug Candidates

“…Structures and activities of representative A) cinnamate and B) oxazole piperazinones modified at the para position of the phenyl ring.Finally, the authors came back on the C-6 position of the piperazinone core by replacing the isobutyl group with either different hydrophobic moieties (acyclic, branched, cyclic, and saturated/unsaturated alkyls) or alkyl and aryl substituents having H-bond acceptor or donor properties [118][119][120]. In general, acyclic and cyclic alkyls (e.g.…”