RESUMO
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.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Cardiomiopatia Dilatada/tratamento farmacológico , Morfolinas/administração & dosagem , Miócitos Cardíacos/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Volume Sistólico/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Actinas/genética , Administração Oral , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cardiomiopatia Dilatada/enzimologia , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/fisiopatologia , Células Cultivadas , Modelos Animais de Doenças , Predisposição Genética para Doença , Humanos , Camundongos Transgênicos , Morfolinas/farmacocinética , Mutação , Miócitos Cardíacos/enzimologia , Fosforilação , Inibidores de Proteínas Quinases/farmacocinética , Ratos , Recuperação de Função FisiológicaRESUMO
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.
Assuntos
Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Oxidiazóis/farmacologia , Tiadiazóis/farmacologia , Diacilglicerol O-Aciltransferase/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Tiadiazóis/químicaRESUMO
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.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Adamantano/química , Adamantano/farmacocinética , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Hipoglicemiantes/síntese química , Tiadiazóis/síntese química , Triglicerídeos/antagonistas & inibidores , Células CACO-2 , Ensaios Clínicos como Assunto , Diacilglicerol O-Aciltransferase/metabolismo , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Humanos , Hipoglicemiantes/farmacologia , Modelos Moleculares , Estereoisomerismo , Relação Estrutura-Atividade , Tiadiazóis/farmacologia , Triglicerídeos/biossínteseRESUMO
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.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Inibidores Enzimáticos/química , Pirazóis/química , Pirrolidinas/química , Ureia/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Administração Oral , Animais , Sítios de Ligação , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Ureia/síntese química , Ureia/farmacocinéticaRESUMO
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.
Assuntos
Catepsina K/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Nitrilas/síntese química , Nitrilas/farmacologia , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Desenho de Fármacos , Descoberta de Drogas , Indicadores e Reagentes , Modelos Moleculares , Curva ROC , Relação Estrutura-Atividade , Torsades de Pointes/tratamento farmacológicoRESUMO
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.
Assuntos
Catepsinas/antagonistas & inibidores , Nitrilas/química , Inibidores de Proteases/química , Purinas/química , Domínio Catalítico , Catepsina K/antagonistas & inibidores , Catepsina K/metabolismo , Catepsinas/metabolismo , Linhagem Celular , Simulação por Computador , Humanos , Nitrilas/síntese química , Nitrilas/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Purinas/síntese química , Purinas/farmacologia , Pirimidinas/químicaRESUMO
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%.
Assuntos
Catepsina K/antagonistas & inibidores , Inibidores de Cisteína Proteinase/química , Pirimidinas/química , Administração Oral , Animais , Sítios de Ligação , Catepsina K/metabolismo , Linhagem Celular , Cristalografia por Raios X , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/farmacocinética , Desenho de Fármacos , Ensaios de Triagem em Larga Escala , Humanos , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Barreira Hematoencefálica , Análise Discriminante , Avaliação Pré-Clínica de Medicamentos , Relação Quantitativa Estrutura-AtividadeRESUMO
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.
Assuntos
Antígeno-1 Associado à Função Linfocitária/metabolismo , Compostos de Espiro/síntese química , Tiofenos/síntese química , Animais , Adesão Celular/efeitos dos fármacos , Cristalografia por Raios X , Cães , Rejeição de Enxerto/prevenção & controle , Humanos , Antígeno-1 Associado à Função Linfocitária/química , Camundongos , Modelos Moleculares , Estrutura Molecular , Pneumonia/tratamento farmacológico , Pneumonia/imunologia , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/farmacocinética , Tiofenos/farmacologia , Transplante HomólogoRESUMO
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.
Assuntos
Ligantes , Relação Quantitativa Estrutura-Atividade , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Técnicas de Química Combinatória , Desenho de Fármacos , Modelos Moleculares , Ensaio Radioligante , Receptores de Quimiocinas/química , Receptores de Quimiocinas/metabolismo , Receptores de Peptídeos/química , Receptores de Peptídeos/metabolismoRESUMO
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.