ABSTRACT
A high throughput screen allowed the identification of N-hydroxyimide inhibitors of ERCC1-XPF endonuclease activity with micromolar potency, but they showed undesirable selectivity profiles against FEN-1. A scaffold hop to a hydroxypyrimidinone template gave compounds with similar potency but allowed selectivity to be switched in favour of ERCC1-XPF over FEN-1. Further exploration of the structure-activity relationships around this chemotype gave sub-micromolar inhibitors with >10-fold selectivity for ERCC1-XPF over FEN-1.
Subject(s)
DNA-Binding Proteins/antagonists & inhibitors , Endonucleases/antagonists & inhibitors , Imides/pharmacology , Pyrimidinones/pharmacology , DNA Repair , Dose-Response Relationship, Drug , Flap Endonucleases/antagonists & inhibitors , Hep G2 Cells , Humans , Imides/chemistry , Molecular Structure , Pyrimidinones/chemistry , Structure-Activity RelationshipABSTRACT
Catechol-based inhibitors of ERCC1-XPF endonuclease activity were identified from a high-throughput screen. Exploration of the structure-activity relationships within this series yielded compound 13, which displayed an ERCC1-XPF IC50 of 0.6 µM, high selectivity against FEN-1 and DNase I and activity in nucleotide excision repair, cisplatin enhancement and γH2AX assays in A375 melanoma cells. Screening of fragments as potential alternatives to the catechol group revealed that 3-hydroxypyridones are able to inhibit ERCC1-XPF with high ligand efficiency, and elaboration of the hit gave compounds 36 and 37 which showed promising ERCC1-XPF IC50 values of <10 µM.
Subject(s)
Catechols/pharmacology , DNA Repair/drug effects , DNA-Binding Proteins/antagonists & inhibitors , Endonucleases/antagonists & inhibitors , Pyridones/pharmacology , Catechols/chemistry , Cell Line, Tumor , Deoxyribonuclease I/antagonists & inhibitors , Deoxyribonuclease I/metabolism , Dose-Response Relationship, Drug , Flap Endonucleases/antagonists & inhibitors , Humans , Molecular Structure , Pyridones/chemistry , Structure-Activity RelationshipABSTRACT
The generation of carbon radicals by halogen-atom and group transfer reactions is generally achieved using tin and silicon reagents that maximize the interplay of enthalpic (thermodynamic) and polar (kinetic) effects. In this work, we demonstrate a distinct reactivity mode enabled by quantum mechanical tunneling that uses the cyclohexadiene derivative γ-terpinene as the abstractor under mild photochemical conditions. This protocol activates alkyl and aryl halides as well as several alcohol and thiol derivatives. Experimental and computational studies unveiled a noncanonical pathway whereby a cyclohexadienyl radical undergoes concerted aromatization and halogen-atom or group abstraction through the reactivity of an effective H atom. This activation mechanism is seemingly thermodynamically and kinetically unfavorable but is rendered feasible through quantum tunneling.
ABSTRACT
Starting from compound 1, we utilized biostructural data to successfully evolve an existing series into a new chemotype with a promising overall profile, exemplified by 19.
Subject(s)
Drug Design , Indans/chemistry , Indans/pharmacology , Receptors, AMPA/metabolism , Sulfonamides/chemistry , Sulfonamides/pharmacology , Allosteric Regulation , Animals , Cell Line , Crystallography, X-Ray , Humans , Indans/metabolism , Indans/pharmacokinetics , Microsomes, Liver/metabolism , Models, Molecular , Nervous System Diseases/drug therapy , Nervous System Diseases/metabolism , Pyrazoles/chemistry , Pyrazoles/metabolism , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Rats , Rats, Wistar , Structure-Activity Relationship , Sulfonamides/metabolism , Sulfonamides/pharmacokineticsABSTRACT
Starting from an HTS derived hit 1, application of biostructural data facilitated rapid optimization to lead 22, a novel AMPA receptor modulator. This is the first demonstration of how structure based drug design can be exploited in an optimization program for a glutamate receptor.
Subject(s)
Indazoles/chemistry , Receptors, AMPA/chemistry , Thiophenes/chemistry , Allosteric Regulation , Animals , Binding Sites , Crystallography, X-Ray , Drug Design , Drug Evaluation, Preclinical , High-Throughput Screening Assays , Humans , Indazoles/chemical synthesis , Indazoles/pharmacology , Microsomes/metabolism , Protein Structure, Tertiary , Rats , Receptors, AMPA/metabolism , Thiophenes/chemical synthesis , Thiophenes/pharmacologyABSTRACT
Starting from lead compound 1, we demonstrate how X-ray structural data can be used to understand SAR and expediently optimize bioavailability in a novel series of AMPA receptor modulators, furnishing 5 with improved bioavailability and robust in vivo activity.