RESUMO
Optimisation of a series of benzazepine sulfonamide hit compounds identified from high throughput screening led to the discovery of a new series of tractable, potent motilin receptor agonists.
Assuntos
Receptores dos Hormônios Gastrointestinais/agonistas , Receptores de Neuropeptídeos/agonistas , Sulfonamidas/farmacologia , Sulfonas/farmacologia , Animais , Sítios de Ligação , Células CHO , Química Farmacêutica , Cricetinae , Cricetulus , Desenho de Fármacos , Descoberta de Drogas , Modelos Químicos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A series of 2-aminomethyl piperidines has been discovered as novel urotensin-II receptor antagonists. The synthesis, initial structure-activity relationships, and optimization of the initial hit that resulted in the identification of potent, cross-species active, and functional urotensin-II receptor antagonists such as 1a and 11a are described.
Assuntos
Metilaminas/farmacologia , Piperidinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Vasoconstritores/farmacologia , Sítios de Ligação , Humanos , Metilaminas/síntese química , Modelos Químicos , Piperidinas/síntese química , Estereoisomerismo , Relação Estrutura-Atividade , Vasoconstritores/síntese químicaRESUMO
High-throughput screening resulted in the identification of a series of novel motilin receptor agonists with relatively low molecular weights. The series originated from an array of biphenyl derivatives designed to target 7-transmembrane (7-TM) receptors. Further investigation of the structure-activity relationship within the series resulted in the identification of compound (22) as a potent and selective agonist at the motilin receptor.
Assuntos
Receptores dos Hormônios Gastrointestinais/agonistas , Receptores dos Hormônios Gastrointestinais/química , Receptores de Neuropeptídeos/agonistas , Receptores de Neuropeptídeos/química , Animais , Sítios de Ligação , Membrana Celular/metabolismo , Química Farmacêutica/métodos , Técnicas de Química Combinatória , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Modelos Químicos , Estrutura Molecular , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Recombinantes/química , Relação Estrutura-AtividadeRESUMO
Pulmonary edema is a common ailment of heart failure patients and has remained an unmet medical need due to dose-limiting side effects associated with current treatments. Preclinical studies in rodents have suggested that inhibition of transient receptor potential vanilloid-4 (TRPV4) cation channels may offer an alternative-and potentially superior-therapy. Efforts directed toward small-molecule antagonists of the TRPV4 receptor have led to the discovery of a novel sulfone pyrrolidine sulfonamide chemotype exemplified by lead compound 6. Design elements toward the optimization of TRPV4 activity, selectivity, and pharmacokinetic properties are described. Activity of leading exemplars 19 and 27 in an in vivo model suggestive of therapeutic potential is highlighted herein.
Assuntos
Edema Pulmonar/tratamento farmacológico , Pirrolidinas/farmacologia , Sulfonamidas/farmacologia , Sulfonas/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Pirrolidinas/química , Pirrolidinas/farmacocinética , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonas/química , Sulfonas/farmacocinéticaRESUMO
Pulmonary edema resulting from high pulmonary venous pressure (PVP) is a major cause of morbidity and mortality in heart failure (HF) patients, but current treatment options demonstrate substantial limitations. Recent evidence from rodent lungs suggests that PVP-induced edema is driven by activation of pulmonary capillary endothelial transient receptor potential vanilloid 4 (TRPV4) channels. To examine the therapeutic potential of this mechanism, we evaluated TRPV4 expression in human congestive HF lungs and developed small-molecule TRPV4 channel blockers for testing in animal models of HF. TRPV4 immunolabeling of human lung sections demonstrated expression of TRPV4 in the pulmonary vasculature that was enhanced in sections from HF patients compared to controls. GSK2193874 was identified as a selective, orally active TRPV4 blocker that inhibits Ca(2+) influx through recombinant TRPV4 channels and native endothelial TRPV4 currents. In isolated rodent and canine lungs, TRPV4 blockade prevented the increased vascular permeability and resultant pulmonary edema associated with elevated PVP. Furthermore, in both acute and chronic HF models, GSK2193874 pretreatment inhibited the formation of pulmonary edema and enhanced arterial oxygenation. Finally, GSK2193874 treatment resolved pulmonary edema already established by myocardial infarction in mice. These findings identify a crucial role for TRPV4 in the formation of HF-induced pulmonary edema and suggest that TRPV4 blockade is a potential therapeutic strategy for HF patients.
Assuntos
Insuficiência Cardíaca/complicações , Moduladores de Transporte de Membrana/administração & dosagem , Moduladores de Transporte de Membrana/uso terapêutico , Edema Pulmonar/tratamento farmacológico , Edema Pulmonar/prevenção & controle , Canais de Cátion TRPV/antagonistas & inibidores , Administração Oral , Animais , Pressão Sanguínea/efeitos dos fármacos , Cálcio/metabolismo , Modelos Animais de Doenças , Diuréticos/farmacologia , Endotélio/efeitos dos fármacos , Endotélio/metabolismo , Endotélio/patologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Técnicas In Vitro , Ativação do Canal Iônico/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Moduladores de Transporte de Membrana/química , Moduladores de Transporte de Membrana/farmacologia , Camundongos , Camundongos Knockout , Permeabilidade/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Edema Pulmonar/etiologia , Edema Pulmonar/patologia , Ratos , Canais de Cátion TRPV/metabolismo , Equilíbrio Hidroeletrolítico/efeitos dos fármacosRESUMO
Bacterial enoyl-acyl carrier protein (ACP) reductase (FabI) catalyzes the final step in each elongation cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. High-throughput screening of the Staphylococcus aureus FabI enzyme identified a novel, weak inhibitor with no detectable antibacterial activity against S. aureus. Iterative medicinal chemistry and X-ray crystal structure-based design led to the identification of compound 4 [(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide], which is 350-fold more potent than the original lead compound obtained by high-throughput screening in the FabI inhibition assay. Compound 4 has exquisite antistaphylococci activity, achieving MICs at which 90% of isolates are inhibited more than 500 times lower than those of nine currently available antibiotics against a panel of multidrug-resistant strains of S. aureus and Staphylococcus epidermidis. Furthermore, compound 4 exhibits excellent in vivo efficacy in an S. aureus infection model in rats. Biochemical and genetic approaches have confirmed that the mode of antibacterial action of compound 4 and related compounds is via inhibition of FabI. Compound 4 also exhibits weak FabK inhibitory activity, which may explain its antibacterial activity against Streptococcus pneumoniae and Enterococcus faecalis, which depend on FabK and both FabK and FabI, respectively, for their enoyl-ACP reductase function. These results show that compound 4 is representative of a new, totally synthetic series of antibacterial agents that has the potential to provide novel alternatives for the treatment of S. aureus infections that are resistant to our present armory of antibiotics.