RESUMO
High-throughput screening resulted in the identification of a series of novel motilin receptor agonists with relatively low molecular weights. The series originated from an array of biphenyl derivatives designed to target 7-transmembrane (7-TM) receptors. Further investigation of the structure-activity relationship within the series resulted in the identification of compound (22) as a potent and selective agonist at the motilin receptor.
Assuntos
Receptores dos Hormônios Gastrointestinais/agonistas , Receptores dos Hormônios Gastrointestinais/química , Receptores de Neuropeptídeos/agonistas , Receptores de Neuropeptídeos/química , Animais , Sítios de Ligação , Membrana Celular/metabolismo , Química Farmacêutica/métodos , Técnicas de Química Combinatória , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Modelos Químicos , Estrutura Molecular , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Recombinantes/química , Relação Estrutura-AtividadeRESUMO
Optimisation of urea (5), identified from high throughput screening and subsequent array chemistry, has resulted in the identification of pyridine carboxamide (33) which is a potent motilin receptor agonist possessing favourable physicochemical and ADME profiles. Compound (33) has demonstrated prokinetic-like activity both in vitro and in vivo in the rabbit and therefore represents a promising novel small molecule motilin receptor agonist for further evaluation as a gastroprokinetic agent.
Assuntos
Carbono/química , Piridinas/química , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores de Neuropeptídeos/agonistas , Animais , Química Farmacêutica/métodos , Desenho de Fármacos , Gastrinas/química , Humanos , Concentração Inibidora 50 , Cinética , Modelos Químicos , Piridinas/síntese química , Piridinas/farmacologia , Coelhos , Ratos , Receptores dos Hormônios Gastrointestinais/química , Receptores de Neuropeptídeos/químicaRESUMO
Spleen tyrosine kinase (Syk) is an intriguing protein tyrosine kinase involved in signal transduction in a variety of cell types, and its aberrant regulation is associated with different allergic disorders and antibody-mediated autoimmune diseases such as rheumatoid arthritis, asthma and allergic rhinitis. Syk also plays an important part in the uncontrolled growth of tumor cells, particularly B cells. For these reasons, Syk is considered one of the most interesting biological targets of the last decade, as proved by the great number of papers and patents published, and the possibility of treating these pathologies by means of Syk kinase inhibitors has led to a great interest from the pharmaceutical and biotech industry.