ABSTRACT
Recently, we disclosed a new class of HCV polymerase inhibitors discovered through high-throughput screening (HTS) of the GlaxoSmithKline proprietary compound collection. This interesting class of 3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones potently inhibits HCV polymerase enzymatic activity and inhibits the ability of the subgenomic HCV replicon to replicate in Huh-7 cells. This report will focus on the structure-activity relationships (SAR) of substituents on the quinolinone ring, culminating in the discovery of 1-(2-cyclopropylethyl)-3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-6-fluoro-4-hydroxy-2(1H)-quinolinone (130), an inhibitor with excellent potency in biochemical and cellular assays possessing attractive molecular properties for advancement as a clinical candidate. The potential for development and safety assessment profile of compound 130 will also be discussed.
Subject(s)
Antiviral Agents/chemical synthesis , Benzothiadiazines/chemical synthesis , Hepacivirus/enzymology , Quinolones/chemical synthesis , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Thiadiazines/chemical synthesis , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Benzothiadiazines/chemistry , Benzothiadiazines/pharmacology , Biological Availability , Blood Proteins/metabolism , Cell Line , Crystallography, X-Ray , Dogs , Genotype , Half-Life , Hepacivirus/genetics , Macaca fascicularis , Models, Molecular , Molecular Structure , Mutation , Protein Binding , Quinolones/chemistry , Quinolones/pharmacology , RNA-Dependent RNA Polymerase/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Thiadiazines/chemistry , Thiadiazines/pharmacologyABSTRACT
A simple, novel, and efficient route for the synthesis of 5-amino-3-aryl-1-(tert-butyl)-1H-pyrazole-4-carboxamides 1 has been devised. Preparation of pyrazole bromide 3 from potassium tricyanomethanide can be accomplished in only two steps in good yield and features a selective Sandmeyer reaction on the corresponding diaminopyrazole. This allows for a more versatile synthesis of 5-amino-3-aryl-1-(tert-butyl)-1H-pyrazole-4-carboxamides 1 than was previously possible.
Subject(s)
Amides/chemical synthesis , Hydrocarbons, Brominated/chemical synthesis , Pyrazoles/chemical synthesis , Amides/chemistry , Combinatorial Chemistry Techniques , Hydrocarbons, Brominated/chemistry , Molecular Structure , Pyrazoles/chemistry , StereoisomerismABSTRACT
The design of conformationally restricted eight-membered ring diketones as transition state mimics of the mechanism of action of cyclotheonamides on serine proteases is described. Two target compounds are prepared from mutilin, derived from the natural product pleuromutilin. Compound 3 shows significant inhibition of plasmin and urokinase in enzyme rate assays, but an analogue 4 in which the amide moiety has been omitted does not. An X-ray crystal structure of the diketone 3 confirms the conformational predictions made by molecular modelling.