RESUMEN
The discovery of potent small molecule dual antagonists of the human CCR3 and H(1) receptors is described for the treatment of allergic diseases, for example, asthma and allergic rhinitis. Optimizing in vitro potency and metabolic stability, starting from a CCR1 lead compound, led to compound 20 with potent dual CCR3/H(1) activity and in vitro metabolic stability.
Asunto(s)
Descubrimiento de Drogas , Ácidos Hidroxámicos/farmacología , Piperidinas/farmacología , Receptores CCR3/antagonistas & inhibidores , Receptores Histamínicos H1/metabolismo , Animales , Hepatocitos/química , Hepatocitos/metabolismo , Humanos , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/metabolismo , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Piperidinas/química , Piperidinas/metabolismo , Ratas , Relación Estructura-Actividad , Distribución TisularRESUMEN
The second part of this communication focuses on the resolution of issues surrounding the series of hydroxyamide phenoxypiperidine CCR3/H(1) dual antagonists described in Part I. This involved further structural exploration directed at reducing metabolism and leading to the identification of compound 60 with a greatly improved in vivo pharmacokinetic profile.
Asunto(s)
Descubrimiento de Drogas , Piperidinas/farmacología , Receptores CCR3/antagonistas & inhibidores , Receptores Histamínicos H1/metabolismo , Animales , Perros , Hepatocitos/química , Hepatocitos/metabolismo , Humanos , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Piperidinas/química , Piperidinas/metabolismo , Ratas , Relación Estructura-Actividad , Distribución TisularRESUMEN
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.
Asunto(s)
Inhibidores Enzimáticos/química , Isoxazoles/química , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Piridinas/química , Animales , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Isoxazoles/síntesis química , Isoxazoles/farmacología , Ratones , Microsomas Hepáticos/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Estructura Terciaria de Proteína , Piridinas/farmacología , RatasRESUMEN
BACE1 is responsible for the first step in APP proteolysis, leading to toxic Aß production, and has been indicated to play a key role in the pathogenesis of Alzheimer's disease. The related isoform BACE2 is thought to be involved in processing of the pigment cell-specific melanocyte protein. To avoid potential effects on pigmentation, we investigated the feasibility for developing isoform-selective BACE1 inhibitors. Cocrystal structures of 47 compounds were analyzed and clustered according to their selectivity profiles. Selective BACE1 inhibitors were found to exhibit two distinct conformational features proximal to the flap and the S3 subpocket. Several new molecules were designed and tested to make use of this observation. The combination of a pyrimidinyl C-ring and a methylcyclohexyl element resulted in lead molecule 28, which exhibited â¼50-fold selectivity. Compared to a nonselective BACE1/2 inhibitor, 28 showed significantly less inhibition of PMEL processing in human melanocytes, indicating good functional selectivity of this inhibitor class.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores de Proteasas/farmacología , Secretasas de la Proteína Precursora del Amiloide/química , Péptidos beta-Amiloides/metabolismo , Animales , Ácido Aspártico Endopeptidasas/química , Encéfalo/metabolismo , Dominio Catalítico , Perros , Femenino , Humanos , Células de Riñón Canino Madin Darby , Masculino , Ratones Endogámicos C57BL , Estructura Molecular , Oxazoles/síntesis química , Oxazoles/química , Oxazoles/farmacocinética , Oxazoles/farmacología , Fragmentos de Péptidos/metabolismo , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacocinética , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/química , Ratas , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Relación Estructura-Actividad , Antígeno gp100 del Melanoma/metabolismoRESUMEN
The discovery of a novel class of nitric oxide synthase (NOS) inhibitors, 2-substituted 1,2-dihydro-4-quinazolinamines, and the related 4'-aminospiro[piperidine-4,2'(1'H)-quinazolin]-4'-amines is described. Members of both series exhibit nanomolar potency and high selectivity for the inducible isoform of the enzyme (i-NOS) relative to the constitutive isoforms in vitro. Efficacy in acute and chronic animal models of inflammatory disease following oral administration has also been demonstrated using these compounds.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Óxido Nítrico Sintasa/antagonistas & inhibidores , Quinazolinas/síntesis química , Enfermedad Aguda , Administración Oral , Aminas/síntesis química , Aminas/química , Aminas/farmacología , Animales , Artritis Experimental/tratamiento farmacológico , Línea Celular , Enfermedad Crónica , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inyecciones Intravenosas , Isoenzimas/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II , Quinazolinas/química , Quinazolinas/farmacología , Ratas , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
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.