ABSTRACT
AIMS: Despite improvements in patient identification and management, heart failure (HF) remains a major public health burden and an important clinical challenge. A variety of animal and human studies have provided evidence suggesting a central role of calcium/calmodulin-dependent protein kinase II (CaMKII) in the development of pathological cardiac remodelling and HF. Here, we describe a new potent, selective, and orally available CaMKII inhibitor. METHODS AND RESULTS: Chemical optimization led to the identification of RA306 as a selective CaMKII inhibitor. This compound was found potent on the cardiac CaMKII isoforms delta and gamma (IC50 in the 10 nM range), with pharmacokinetic properties allowing oral administration in animal models of HF. RA306 was administered to diseased mice carrying a mutation in alpha-actin that is responsible for dilated cardiomyopathy (DCM) in humans. In two separate studies, RA306 was orally administered at 30 mg/kg either for 2 weeks (twice a day) or for 2 months (once a day). Echocardiography monitoring showed that RA306 significantly improved cardiac function (ejection fraction and cardiac output) as compared to vehicle. These disease modifying effects of RA306 were associated with inhibition of cardiac phosphorylation of phospholamban (PLN) at threonine-17, indicating reduced cardiac CaMKII activity. CONCLUSION: This work supports the feasibility of identifying potent orally available CaMKII inhibitors suitable for clinical use to treat heart disease.
Subject(s)
Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & inhibitors , Cardiomyopathy, Dilated/drug therapy , Morpholines/administration & dosage , Myocytes, Cardiac/drug effects , Protein Kinase Inhibitors/administration & dosage , Stroke Volume/drug effects , Ventricular Function, Left/drug effects , Actins/genetics , Administration, Oral , Animals , Calcium-Binding Proteins/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Cardiomyopathy, Dilated/enzymology , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/physiopathology , Cells, Cultured , Disease Models, Animal , Genetic Predisposition to Disease , Humans , Mice, Transgenic , Morpholines/pharmacokinetics , Mutation , Myocytes, Cardiac/enzymology , Phosphorylation , Protein Kinase Inhibitors/pharmacokinetics , Rats , Recovery of FunctionABSTRACT
Chemical modulation of a formerly disclosed DGAT-1 inhibitor resulted in the identification of a compound with a suitable profile for preclinical development. Optimisation of solubility is discussed and a PK/PD study is presented.
Subject(s)
Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Oxadiazoles/pharmacology , Thiadiazoles/pharmacology , Diacylglycerol O-Acyltransferase/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Humans , Models, Molecular , Molecular Structure , Oxadiazoles/chemical synthesis , Oxadiazoles/chemistry , Structure-Activity Relationship , Thiadiazoles/chemical synthesis , Thiadiazoles/chemistryABSTRACT
Starting from 11ß-HSD1 inhibitors that were active ex vivo but with Cyp 3A4 liability, we obtained a new series of adamantane ureas displaying potent inhibition of both human and rodent 11ß-HSD1 enzymes, devoid of Cyp 3A4 interactions, and rationally designed to provide long-lasting inhibition in target tissues. Final optimizations lead to SAR184841 with good oral pharmacokinetic properties showing in vivo activity and improvement of metabolic parameters in a physiopathological model of type 2 diabetes.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Adamantane/pharmacology , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Adamantane/chemistry , Adamantane/pharmacokinetics , Animals , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 2/metabolism , Disease Models, Animal , Humans , Mice , Mice, Transgenic , Structure-Activity RelationshipABSTRACT
A novel class of DGAT1 inhibitors containing a thiadiazole core has been discovered. Chemical optimization lead to inhibitors of human DGAT1 with an appropriate ADME profile and that show in vivo activity in target tissues.
Subject(s)
Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Thiadiazoles/chemical synthesis , Triglycerides/antagonists & inhibitors , Caco-2 Cells , Clinical Trials as Topic , Diacylglycerol O-Acyltransferase/metabolism , Drug Discovery , Enzyme Inhibitors/pharmacology , Humans , Hypoglycemic Agents/pharmacology , Models, Molecular , Stereoisomerism , Structure-Activity Relationship , Thiadiazoles/pharmacology , Triglycerides/biosynthesisABSTRACT
A High Throughput Screening campaign allowed the identification of a novel class of ureas as 11ß-HSD1 inhibitors. Rational chemical optimization provided potent and selective inhibitors of both human and murine 11ß-HSD1 with an appropriate ADME profile and ex vivo activity in target tissues.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Pyrazoles/chemistry , Pyrrolidines/chemistry , Urea/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Administration, Oral , Animals , Binding Sites , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , High-Throughput Screening Assays , Humans , Mice , Urea/chemical synthesis , Urea/pharmacokineticsABSTRACT
Several structure-guided optimisation strategies were explored in order to improve the hERG selectivity profile of cathepsin K inhibitor 1, whilst maintaining its otherwise excellent in vitro and in vivo profile. Ultimately, attenuation of clogP and pK(a) properties proved a successful approach and led to the discovery of a potent analogue 23, which, in addition to the desired selectivity over hERG (>1000-fold), displayed a highly attractive overall profile.
Subject(s)
Cathepsin K/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/drug effects , Nitriles/chemical synthesis , Nitriles/pharmacology , Potassium Channel Blockers/chemical synthesis , Potassium Channel Blockers/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Drug Design , Drug Discovery , Indicators and Reagents , Models, Molecular , ROC Curve , Structure-Activity Relationship , Torsades de Pointes/drug therapyABSTRACT
Starting from previously disclosed equally potent cathepsin K and S inhibitor 4-propyl-6-(3-trifluoromethylphenyl)pyrimidine-2-carbonitrile 1, a novel 2-phenyl-9H-purine-6-carbonitrile scaffold was identified to provide potent and selective cathepsin S inhibitors.
Subject(s)
Cathepsins/antagonists & inhibitors , Nitriles/chemistry , Protease Inhibitors/chemistry , Purines/chemistry , Catalytic Domain , Cathepsin K/antagonists & inhibitors , Cathepsin K/metabolism , Cathepsins/metabolism , Cell Line , Computer Simulation , Humans , Nitriles/chemical synthesis , Nitriles/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Purines/chemical synthesis , Purines/pharmacology , Pyrimidines/chemistryABSTRACT
Morphing structural features of HTS-derived chemotypes led to the discovery of novel 2-cyano-pyrimidine inhibitors of cathepsin K with good pharmacokinetic profiles, for example, compound 20 showed high catK potency (IC(50)=4nM), >580-fold selectivity over catL and catB, and oral bioavailability in the rat of 52%.
Subject(s)
Cathepsin K/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemistry , Pyrimidines/chemistry , Administration, Oral , Animals , Binding Sites , Cathepsin K/metabolism , Cell Line , Crystallography, X-Ray , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/pharmacokinetics , Drug Design , High-Throughput Screening Assays , Humans , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
A QSAR model aimed at predicting central nervous system (CNS) activity was developed based on the structure-activity relationships of compounds from an in-house database of "drug-like" molecules. These compounds were initially identified as "CNS-active" or "CNS-inactive", and pharmacophore 3D descriptors were calculated from multiple conformations for each structure. A linear discriminant analysis (LDA) was performed on this structure-activity matrix, and this QSAR model was able to correctly classify approximately 80 % in both a learning set and a validation set. For validation purposes, the LDA model was applied to compounds for which the blood-brain barrier (BBB) penetration was known, and all of them were correctly predicted. The model was also applied to 960 other in-house compounds for which in vitro binding tests were performed on 20 receptors known to be present at the CNS level, and a high correlation was observed between compounds predicted as CNS-active and experimental hits. Finally, the model was also applied to a set of 700 structures with known CNS activity or inactivity randomly chosen from public sources, and more than 70 % of the compounds were correctly classified, including novel CNS chemotypes. These results demonstrate the applicability of the model to novel chemical structures and its usefulness for designing original CNS-focused compound libraries.
Subject(s)
Central Nervous System/drug effects , Blood-Brain Barrier , Discriminant Analysis , Drug Evaluation, Preclinical , Quantitative Structure-Activity RelationshipABSTRACT
LFA-1 (leukocyte function-associated antigen-1), is a member of the beta2-integrin family and is expressed on all leukocytes. This letter describes the discovery and preliminary SAR of spirocyclic hydantoin based LFA-1 antagonists that culminated in the identification of analog 8 as a clinical candidate. We also report the first example of the efficacy of a small molecule LFA-1 antagonist in combination with CTLA-4Ig in an animal model of transplant rejection.
Subject(s)
Lymphocyte Function-Associated Antigen-1/metabolism , Spiro Compounds/chemical synthesis , Thiophenes/chemical synthesis , Animals , Cell Adhesion/drug effects , Crystallography, X-Ray , Dogs , Graft Rejection/prevention & control , Humans , Lymphocyte Function-Associated Antigen-1/chemistry , Mice , Models, Molecular , Molecular Structure , Pneumonia/drug therapy , Pneumonia/immunology , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Stereoisomerism , Structure-Activity Relationship , Thiophenes/pharmacokinetics , Thiophenes/pharmacology , Transplantation, HomologousABSTRACT
A QSAR model accounting for "average" G-protein-coupled receptor (GPCR) binding was built from a large set of experimental standardized binding data (1939 compounds systematically tested over 40 different GPCRs) and applied to the design of a library of "GPCR-predicted" compounds. Three hundred and sixty of these compounds were randomly selected and tested in 21 GPCR binding assays. Positives were defined by their ability to inhibit by more than 70% the binding of reference compounds at 10 microM. A 5.5-fold enrichment in positives was observed when comparing the "GPCR-predicted" compounds with 600 randomly selected compounds predicted as "non-GPCR" from a general collection. The model was efficient in predicting strongest binders, since enrichment was greater for higher cutoffs. Significant enrichment was also observed for peptidic GPCRs and receptors not included to develop the QSAR model, suggesting the usefulness of the model to design ligands binding with newly identified GPCRs, including orphan ones.
Subject(s)
Ligands , Quantitative Structure-Activity Relationship , Receptors, G-Protein-Coupled/chemistry , Receptors, G-Protein-Coupled/metabolism , Combinatorial Chemistry Techniques , Drug Design , Models, Molecular , Radioligand Assay , Receptors, Chemokine/chemistry , Receptors, Chemokine/metabolism , Receptors, Peptide/chemistry , Receptors, Peptide/metabolismABSTRACT
LFA-1 (leukocyte function-associated antigen-1), is a member of the beta(2)-integrin family and is expressed on all leukocytes. The LFA-1/ICAM interaction promotes tight adhesion between activated leukocytes and the endothelium, as well as between T cells and antigen-presenting cells. Evidence from both animal models and clinical trials provides support for LFA-1 as a target in several different inflammatory diseases. This paper describes the de novo design, synthesis and in vitro activity of LFA-1 antagonists based on a bicyclic[5.5]hydantoin scaffold.
