RESUMO
Scaffolds of natural products represent promising starting points for the development of focused compound libraries. Here, we describe the development of a synthetic route to a compound library based on the hexahydropyrrolo indole (HPI) scaffold, the denoting structural motif of the HPI natural product family. To this end, a two-step approach consisting of a batch synthesis of an advanced functionalizable HPI intermediate followed by the establishment of reaction conditions that allow derivatization of this scaffold at three different positions is described. Subsequently, the optimized methods were applied to the synthesis of a 276-member library.
Assuntos
Produtos Biológicos/síntese química , Descoberta de Drogas , Indóis/síntese química , Bibliotecas de Moléculas Pequenas/síntese química , Reação de Cicloadição , Estrutura MolecularRESUMO
Libraries of dibasic compounds designed around the molecular scaffold of the DA(2)/ß(2) dual agonist sibenadet (Viozan™) have yielded a number of promising starting points that have been further optimised into novel potent and selective target molecules with required pharmacokinetic properties. From a shortlist, 31 was discovered as a novel, high potency, and highly efficacious ß(2)-agonist with high selectivity and a duration of action commensurable with once daily dosing.
Assuntos
Agonistas Adrenérgicos beta/síntese química , Agonistas Adrenérgicos beta/farmacologia , Química Farmacêutica/métodos , Animais , Asma/tratamento farmacológico , Broncodilatadores/farmacologia , Linhagem Celular Tumoral , AMP Cíclico/metabolismo , Desenho de Fármacos , Cobaias , Humanos , Concentração Inibidora 50 , Modelos Químicos , Ligação Proteica , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tiazóis/farmacologia , Fatores de TempoRESUMO
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
A multifaceted instrumental approach was employed to determine the chemistry and mineralogy of pulverized-coal-combustion fly ashes from two Chinese power plants. Techniques included traditional optical microscopy, X-ray diffraction, and chemical analysis along with a variety of electron beam methods. The aim is to demonstrate and bring together the wide variety of procedures dealing with F as the key element of concern, and determining its location in the mineral nanoparticles. The Hg content of the Anwen (Songzao coalfield) fly ashes is higher than that of the Diandong (East Yunnan) fly ashes, possibly owing to the greater C and Cl in the Anwen fly ashes. Both fly ash sources contain a variety of amorphous and nano-crystalline trace-element-bearing particles, both associated with multi-walled carbon nanotubes and as particles independent of carbons.
Assuntos
Poluentes Atmosféricos/análise , Poluentes Atmosféricos/química , Cinza de Carvão/análise , Cinza de Carvão/química , Carbono/química , China , Espectrometria de Massas , Microscopia Eletrônica , Nanopartículas/análise , Nanopartículas/química , Centrais Elétricas , Espalhamento de Radiação , Análise EspectralRESUMO
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.