RESUMO
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.
Assuntos
Pirimidinas/química , Pirimidinas/farmacologia , Receptores de Interleucina-8B/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Avaliação Pré-Clínica de Medicamentos , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Agonistas Adrenérgicos beta/química , Albuterol/análogos & derivados , Agonistas de Dopamina/química , Relação Quantitativa Estrutura-Atividade , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Agonistas Adrenérgicos beta/síntese química , Agonistas Adrenérgicos beta/farmacologia , Albuterol/farmacocinética , Algoritmos , Animais , Transporte Biológico , Agonistas de Dopamina/síntese química , Agonistas de Dopamina/farmacologia , Desenho de Fármacos , Cobaias , Técnicas In Vitro , Cinética , Modelos Moleculares , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Xinafoato de Salmeterol , Traqueia/efeitos dos fármacos , Traqueia/metabolismo , Traqueia/fisiologiaRESUMO
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.
Assuntos
Catepsina C/antagonistas & inibidores , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Humanos , Indicadores e Reagentes , Modelos Moleculares , Conformação Molecular , Proteínas Recombinantes/química , Espectrometria de Fluorescência , Relação Estrutura-Atividade , Especificidade por Substrato , Difração de Raios XRESUMO
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.
Assuntos
Receptores de Interleucina-8B/antagonistas & inibidores , Tiazóis/farmacologia , Animais , Humanos , Ratos , Receptores de Citocinas/antagonistas & inibidores , Relação Estrutura-Atividade , Tiazóis/químicaRESUMO
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.