RESUMO
The optimization of a new series of muscarinic M(3) antagonists is described, leading to the identification of AZD9164 which was progressed into the clinic for evaluation of its potential as a treatment for COPD.
Assuntos
Antagonistas Muscarínicos/química , Piperidinas/química , Quinuclidinas/química , Receptor Muscarínico M3/agonistas , Proteínas Sanguíneas/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Antagonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Ligação Proteica , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinuclidinas/farmacologia , Quinuclidinas/uso terapêutico , Receptor Muscarínico M3/metabolismo , Relação Estrutura-AtividadeRESUMO
A novel series of biaryl phenoxyacetic acids was discovered as potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). A hit compound 4 was discovered from high throughput screening. Modulation of multiple aryl substituents afforded both agonists and antagonists, with small changes often reversing the mode of action. Understanding the complex SAR allowed design of potent antagonists such as potential candidate 34.
Assuntos
Acetatos/síntese química , Receptores Imunológicos/agonistas , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/agonistas , Receptores de Prostaglandina/antagonistas & inibidores , Acetatos/química , Acetatos/farmacologia , Animais , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
By careful analysis of experimental X-ray ligand crystallographic protein data across several inhibitor series we have discovered a novel, potent and selective series of iNOS inhibitors exemplified by compound 8.
Assuntos
Inibidores Enzimáticos/química , Isoxazóis/química , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Piridinas/química , Animais , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Isoxazóis/síntese química , Isoxazóis/farmacologia , Camundongos , Microssomos Hepáticos/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Estrutura Terciária de Proteína , Piridinas/farmacologia , RatosRESUMO
4-Methylaminopyridine (4-MAP) (5) is a potent but nonselective nitric oxide synthase (NOS) inhibitor. While simple N-methylation in this series results in poor activity, more elaborate N-substitution such as with 4-piperidine carbamate or amide results in potent and selective inducible NOS inhibition. Evidently, a flipping of the pyridine ring between these new inhibitors allows the piperidine to interact with different residues and confer excellent selectivity.
Assuntos
Aminopiridinas/síntese química , Óxido Nítrico Sintase/antagonistas & inibidores , Aminopiridinas/química , Animais , Cristalografia por Raios X , Camundongos , Modelos Moleculares , Óxido Nítrico Sintase/química , Óxido Nítrico Sintase Tipo IIRESUMO
A lead generation and optimization program delivered the highly selective and potent CatC inhibitor 10 as an in vivo tool compound and potential development candidate. Structural studies were undertaken to generate SAR understanding.