ABSTRACT
Inhibitors of the Hsp90 molecular chaperone are showing promise as anti-cancer agents. Here we describe a series of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors that were identified following structure-driven optimization of purine hits revealed by NMR based screening of a proprietary fragment library. Ligand-Hsp90 X-ray structures combined with molecular modeling led to the rational displacement of a conserved water molecule leading to enhanced affinity for Hsp90 as measured by fluorescence polarization, isothermal titration calorimetry and surface plasmon resonance assays. This displacement was achieved with a nitrile group, presenting an example of efficient gain in binding affinity with minimal increase in molecular weight. Some compounds in this chemical series inhibit the proliferation of human cancer cell lines in vitro and cause depletion of oncogenic Hsp90 client proteins and concomitant elevation of the co-chaperone Hsp70. In addition, one compound was demonstrated to be orally bioavailable in the mouse. This work demonstrates the power of structure-based design for the rapid evolution of potent Hsp90 inhibitors and the importance of considering conserved water molecules in drug design.
Subject(s)
Drug Design , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Pyrimidines/chemistry , Pyrroles/chemistry , Water/chemistry , Administration, Oral , Animals , Binding Sites , Cell Line, Tumor , Cell Proliferation/drug effects , HCT116 Cells , HSP90 Heat-Shock Proteins/metabolism , Half-Life , Humans , Male , Mice , Mice, Inbred BALB C , Molecular Docking Simulation , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Pyrroles/chemical synthesis , Pyrroles/pharmacokinetics , Structure-Activity RelationshipABSTRACT
We describe here our attempts to optimise the human fatty acid amide hydrolase (FAAH) inhibition and physicochemical properties of our previously reported tetrasubstituted azetidine urea FAAH inhibitor, VER-156084. We describe the SAR of a series of analogues and conclude with the demonstration of in vivo dose-dependant FAAH inhibition in an anandamide-loading study in rats.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Azetidines/pharmacology , Enzyme Inhibitors/pharmacology , Urea/pharmacology , Amidohydrolases/metabolism , Animals , Azetidines/chemical synthesis , Azetidines/chemistry , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Dose-Response Relationship, Drug , ERG1 Potassium Channel , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Models, Molecular , Molecular Structure , Rats , Stereoisomerism , Structure-Activity Relationship , Urea/chemical synthesis , Urea/chemistryABSTRACT
Antagonists of the human A(2A) receptor have been reported to have potential therapeutic benefit in the alleviation of the symptoms associated with neurodegenerative movement disorders such as Parkinson's disease. As part of our efforts to discover potent and selective antagonists of this receptor, we herein describe the detailed optimization and structure-activity relationships of a series of pyrimidine-4-carboxamides. These optimized derivatives display desirable physiochemical and pharmacokinetic profiles, which have led to promising oral activity in clinically relevant models of Parkinson's disease.
Subject(s)
Adenosine A2 Receptor Antagonists , Parkinson Disease/drug therapy , Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptor, Adenosine A2A/metabolism , Animals , Humans , Locomotion/drug effects , Mice , Protein Binding , Pyrimidines/pharmacokinetics , Pyrimidines/therapeutic use , Structure-Activity RelationshipABSTRACT
We report the discovery of a novel, chiral azetidine urea inhibitor of Fatty Acid Amide Hydrolase (FAAH,) and describe the surprising species selectivity of VER-156084 versus rat and human FAAH and also hCB1.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Amidohydrolases/chemistry , Azetidines/chemistry , Azetidines/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Piperidines/chemical synthesis , Urea/chemistry , Animals , Azetidines/pharmacology , Catalysis , Chemistry, Pharmaceutical/methods , Drug Design , Enzyme Inhibitors/pharmacology , Humans , Mice , Mice, Knockout , Models, Chemical , Piperidines/pharmacology , Rats , Receptor, Cannabinoid, CB1/chemistry , StereoisomerismABSTRACT
A novel series of antagonists of the human A(2A) receptor have been identified and have been shown to display good potency and high degrees of selectivity over other receptor sub-types. Displaying in vivo potency in commonly used disease models and high oral bio-availability, this class of compounds may serve as clinically useful treatments for the relief of the symptoms associated with Parkinson's disease.
Subject(s)
Adenosine A2 Receptor Antagonists , Amides/chemical synthesis , Pyrimidines/chemistry , Administration, Oral , Amides/administration & dosage , Amides/chemistry , Animals , Disease Models, Animal , Humans , Mice , Receptor, Adenosine A2A/metabolismABSTRACT
A series of 1-(1-pyrrolo(iso)quinolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for the compounds at 5-HT(2) receptor subtypes are reported. The analogue which showed the highest 5-HT(2C) binding affinity (27, 1.6nM) was found to be successful in reducing food intake in rats.
