RESUMO
A series of novel biphenyl piperazines was discovered as highly potent muscarinic acetylcholine receptor antagonists via high throughput screening and subsequent optimization. Compound 5c with respective 500- and 20-fold subtype selectivity for M3 over M2 and M1 exhibited excellent inhibitory activity and long duration of action in a bronchoconstriction in vivo model in mice via intranasal administration. The novel inhaled mAChR antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease.
Assuntos
Broncoconstrição/efeitos dos fármacos , Broncodilatadores/farmacologia , Piperazinas/farmacologia , Receptores Muscarínicos/efeitos dos fármacos , Administração Intranasal , Animais , Testes de Provocação Brônquica , Broncoconstritores/farmacologia , Broncodilatadores/síntese química , Broncodilatadores/química , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Cloreto de Metacolina/farmacologia , Camundongos , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
High throughput screening and subsequent optimization led to the discovery of novel quaternary ammonium salts as highly potent muscarinic acetylcholine receptor antagonists with excellent selectivity. Compounds 8a, 13a, and 13b showed excellent inhibitory activity and long duration of action in bronchoconstriction in vivo models in two species via intranasal or intratracheal administration. The novel inhaled muscarinic receptor antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease and other bronchoconstriction disorders.
Assuntos
Antagonistas Muscarínicos/farmacologia , Compostos de Fenilureia/farmacologia , Compostos de Amônio Quaternário/farmacologia , Tirosina/análogos & derivados , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Broncoconstrição/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Cobaias , Camundongos , Ratos , Tirosina/farmacologiaRESUMO
In the course of our research program to develop novel muscarinic receptor antagonists for the treatment of COPD, new tropane carbamate derivatives were identified as potent anti-muscarinic agents. The synthesis, structure-activity relationships and pharmacological evaluation that led to the identification of compound 5o, are described.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Carbamatos/síntese química , Antagonistas Muscarínicos , Receptores Muscarínicos/efeitos dos fármacos , Tropanos/síntese química , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Broncodilatadores/síntese química , Broncodilatadores/química , Broncodilatadores/farmacologia , Carbamatos/química , Carbamatos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Antagonistas Muscarínicos/síntese química , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/farmacologia , Doença Pulmonar Obstrutiva Crônica/terapia , Tropanos/química , Tropanos/farmacologiaRESUMO
High-throughput screening of the corporate compound collection led to the discovery of a novel series of N-substituted-5-aryl-oxazolidinones as potent human CCR8 antagonists. The synthesis, structure-activity relationships, and optimization of the series that led to the identification of SB-649701 (1a), are described.
Assuntos
Oxazolidinonas/síntese química , Oxazolidinonas/farmacologia , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Células CHO , Quimiotaxia de Leucócito/efeitos dos fármacos , Simulação por Computador , Cricetinae , Cricetulus , Avaliação Pré-Clínica de Medicamentos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Indicadores e Reagentes , Miotonina Proteína Quinase , Proteínas Serina-Treonina Quinases/efeitos dos fármacos , Receptores CCR8 , Relação Estrutura-Atividade , Células Th2/efeitos dos fármacosRESUMO
High throughput screening of the corporate compound collection led to the discovery of a novel series of substituted aminoalkoxybenzyl pyrrolidines as human urotensin-II receptor antagonists. The synthesis, initial structure-activity relationships, and optimization of the initial hit that led to the identification of a truncated sub-series, represented by SB-436811 (1a), are described.
Assuntos
Pirrolidinas/síntese química , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Humanos , Pirrolidinas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Much evidence implicates IL-8 as a major mediator of inflammation and joint destruction in rheumatoid arthritis. The effects of IL-8 and its related ligands are mediated via two receptors, CXCR1 and CXCR2. In the present study, we demonstrate that a potent and selective nonpeptide antagonist of human CXCR2 potently inhibits (125)I-labeled human IL-8 binding to, and human IL-8-induced calcium mobilization mediated by, rabbit CXCR2 (IC(50) = 40.5 and 7.7 nM, respectively), but not rabbit CXCR1 (IC(50) = >1000 and 2200 nM, respectively). These data suggest that the rabbit is an appropriate species in which to examine the anti-inflammatory effects of a human CXCR2-selective antagonist. In two acute models of arthritis in the rabbit induced by knee joint injection of human IL-8 or LPS, and a chronic Ag (OVA)-induced arthritis model, administration of the antagonist at 25 mg/kg by mouth twice a day significantly reduced synovial fluid neutrophils, monocytes, and lymphocytes. In addition, in the more robust LPS- and OVA-induced arthritis models, which were characterized by increased levels of proinflammatory mediators in the synovial fluid, TNF-alpha, IL-8, PGE(2), leukotriene B(4), and leukotriene C(4) levels were significantly reduced, as was erythrocyte sedimentation rate, possibly as a result of the observed decreases in serum TNF-alpha and IL-8 levels. In vitro, the antagonist potently inhibited human IL-8-induced chemotaxis of rabbit neutrophils (IC(50) = 0.75 nM), suggesting that inhibition of leukocyte migration into the knee joint is a likely mechanism by which the CXCR2 antagonist modulates disease.