RESUMEN
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.
Asunto(s)
Receptores de la Hormona Gastrointestinal/agonistas , Receptores de la Hormona Gastrointestinal/química , Receptores de Neuropéptido/agonistas , Receptores de Neuropéptido/química , Animales , Sitios de Unión , Membrana Celular/metabolismo , Química Farmacéutica/métodos , Técnicas Químicas Combinatorias , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Modelos Químicos , Estructura Molecular , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Recombinantes/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Carbono/química , Piridinas/química , Receptores de la Hormona Gastrointestinal/agonistas , Receptores de Neuropéptido/agonistas , Animales , Química Farmacéutica/métodos , Diseño de Fármacos , Gastrinas/química , Humanos , Concentración 50 Inhibidora , Cinética , Modelos Químicos , Piridinas/síntesis química , Piridinas/farmacología , Conejos , Ratas , Receptores de la Hormona Gastrointestinal/química , Receptores de Neuropéptido/químicaRESUMEN
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.