RESUMEN
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.
Asunto(s)
Catepsina C/antagonistas & inhibidores , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Humanos , Indicadores y Reactivos , Modelos Moleculares , Conformación Molecular , Proteínas Recombinantes/química , Espectrometría de Fluorescencia , Relación Estructura-Actividad , Especificidad por Sustrato , Difracción de Rayos XRESUMEN
The CXCR2 SAR of a series of bicyclic antagonists such as the 2-aminothiazolo[4,5-d]pyrimidine 3b was investigated by systematic variation of the fused pyrimidine-based heterocyclic cores. Replacement of the aminothiazole ring with a 2-thiazolone alternative led to a series of thiazolo[4,5-d]pyrimidine-2(3H)-one antagonists with markedly improved biological and pharmacokinetic properties, which are suitable pharmacological tools to probe the in vivo effects of CXCR2 antagonism combined with the associated CCR2 activity.
Asunto(s)
Pirimidinas/química , Pirimidinas/farmacología , Receptores de Interleucina-8B/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Evaluación Preclínica de Medicamentos , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
As part of a Lead Optimisation programme to identify small molecule antagonists of the human CXCR2 receptor, a series of substituted thiazolo[4,5-d]pyrimidines was prepared via the application of a novel tandem displacement reaction.
Asunto(s)
Receptores de Interleucina-8B/antagonistas & inhibidores , Tiazoles/farmacología , Animales , Humanos , Ratas , Receptores de Citocinas/antagonistas & inhibidores , Relación Estructura-Actividad , Tiazoles/químicaRESUMEN
This paper describes the development of a QSAR model for the rational control of functional duration of topical long-acting dual D(2)-receptor/beta(2)-adrenoceptor agonists for the treatment of chronic obstructive pulmonary disease. A QSAR model highlighted the importance of lipophilicity and ionization in controlling beta(2) duration. It was found that design rules logD(7.4) > 2, secondary amine pK(a) > 8.0, yielded ultra-long duration compounds. This model was used successfully to guide the design of long- and ultra-long-acting compounds. The QSAR model is discussed in terms of the exosite model, and the plasmalemma diffusion microkinetic hypothesis, for the control of beta(2) duration. Data presented strongly suggests that beta(2) duration is primarily controlled by the membrane affinity of these compounds.
Asunto(s)
Agonistas Adrenérgicos beta/química , Albuterol/análogos & derivados , Agonistas de Dopamina/química , Relación Estructura-Actividad Cuantitativa , Receptores Adrenérgicos beta 2/efectos de los fármacos , Agonistas Adrenérgicos beta/síntesis química , Agonistas Adrenérgicos beta/farmacología , Albuterol/farmacocinética , Algoritmos , Animales , Transporte Biológico , Agonistas de Dopamina/síntesis química , Agonistas de Dopamina/farmacología , Diseño de Fármacos , Cobayas , Técnicas In Vitro , Cinética , Modelos Moleculares , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Xinafoato de Salmeterol , Tráquea/efectos de los fármacos , Tráquea/metabolismo , Tráquea/fisiologíaRESUMEN
The metabolism of 3-([3-(2-Chlorophenyl)-4,5-dihydro-5-thioxo-1H-1,2,4-triazol-1-yl]methyl)benzonitrile (AR-C133611XX) was studied in isolated dog hepatocytes. The major metabolite of AR-C133611XX was characterized by high performance liquid chromatography-mass spectrometry and NMR and found to be the product of direct glucuronidation. Evidence from 1H and 13C-NMR chemical shifts and a long-range proton carbon correlation experiment was used to deduce that glucuronidation had taken place on the sulfur atom. Full NMR data on this unusual metabolite is presented. Substitution or replacement of the sulfur atom resulted in a significant decrease in the observed rate of glucuronidation.
