Inhibitors of HCV NS5B polymerase. Part 2: Evaluation of the northern region of (2Z)-2-benzoylamino-3-(4-phenoxy-phenyl)-acrylic acid

Abstract

A novel series of non-nucleoside HCV NS5B polymerase inhibitors was prepared from a (2Z)-2-benzoylamino-3-(4-phenoxy-phenyl)-acrylic acid template. Solution and solid phase analog synthesis focused on the northern region of the template combined with structure based design led to the discovery of several potent and orally bioavailable lead compounds.

Structural Basis for Resistance of the Genotype 2b Hepatitis C Virus NS5B Polymerase to Site A Non-Nucleoside Inhibitors

“…1). Several classes of compounds are known to bind this site, including benzothiadiazines, 22 phenyl-phenoxy acrylic acids 21,22,31 and the reversible covalent arylsulfonyl rhodanines. 32 X-ray structures of 1bdc21 with inhibitors from each class have been reported.…”

α-Amino acid derivatives with a Cα-P bond in organic synthesis

“…28 Benzyl diethoxyphosphorylacetate (25, R = PhCH 2 ) was aminated with this reagent in THF at -78 o C in the presence of sodium hydride, obtaining the amination product 3a in 60-74% yields. [28][29][30] Electrophilic amination of the α-position of diethoxyphosphorylacetates can also be performed in a few steps, e.g. by the reaction of the enolate anion derived from the ester 25 with ethyl nitrite, followed by the reduction of the obtained oxime 26 with zinc in acetic acid or aluminum amalgam (Scheme 11).…”

“…29 The widest application of α-(dialkoxyphosphoryl)glycinates is their use in the WadsworthEmmons synthesis of α,β-dehydro-α-amino acids. 7,30,38, The latter compounds are common components of naturally occurring peptides; 71,[74][75][76][77] apart from that, their hydrogenation using Wilkinson-type chiral catalysts is considered to be one of the most general methods for the enantioselective synthesis of α-amino acids. [71][72]76 The synthesis of α,β-dehydro-α-amino acids, including their synthesis from α-(dialkoxyphosphoryl)glycinates in the Wadsworth-Emmons reaction, was the subject matter of a few excellent reviews.…”

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of thiazolone derivatives as hepatitis C virus NS5B polymerase allosteric inhibitors

“…It is one of the essential enzymes responsible for HCV viral replication and has attracted most attention as a potential therapeutic target [6]. In the past decade, there have been tremendous efforts dedicated to the development of novel, effective inhibitors of anti-HCV NS5B polymerase, and numerous classes of non-nucleoside inhibitors with different scaffolds have appeared in the literatures, such as benzimidazole [7][8][9], proline sulfonamide [10], indole [11][12][13][14], diketoacid [15][16][17], phenylalanine [18], thiophene [19], pyridazinone [20,21] and acrylic acid [22,23] and so on. Recently, a novel class of HCV NS5B polymerase inhibitors with thiazolone scaffold has been identified by the structurebased design method [24].…”