RESUMEN
The lead optimisation of the diaminopyrimidine carboxamide series of spleen tyrosine kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over liability kinases and hERG activity. GSK143 is a potent and highly selective SYK inhibitor showing good efficacy in the rat Arthus model.
Asunto(s)
Compuestos de Anilina/química , Compuestos de Anilina/uso terapéutico , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Reacción de Arthus/tratamiento farmacológico , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/química , Pirimidinas/uso terapéutico , Administración Oral , Compuestos de Anilina/farmacología , Animales , Antiinflamatorios/farmacología , Cristalografía por Rayos X , Descubrimiento de Drogas , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Modelos Moleculares , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/metabolismo , Pirimidinas/farmacología , Ratas , Relación Estructura-Actividad , Quinasa SykRESUMEN
An enantioselective synthesis of the halogenated medium-ring ether natural product (+)-obtusenyne is reported which uses the ring expansion of a seven-membered ketene acetal by means of a Claisen rearrangement to construct the core nine-membered oxygen heterocycle. The trans substituents across the ether linkage were established by using a transition-metal-catalyzed intramolecular hydrosilation reaction of an exo-cyclic enol ether. In addition, a formal synthesis of ent-obtusenyne from 2-deoxy-D-ribose is reported. A number of interesting points regarding the chemistry of medium-ring oxygen heterocycles are highlighted.
Asunto(s)
Alquinos/síntesis química , Éteres Cíclicos/síntesis química , Alquinos/química , Cristalografía por Rayos X , Éteres Cíclicos/química , Modelos Moleculares , Conformación Molecular , EstereoisomerismoRESUMEN
A series of thiazole based 5HT(7) ligands has been identified from screening. Optimisation of the pendent aryl group and modification of the core gave a related series of high affinity, selective thiopyridine based 5HT(7) ligands, the most active of which behaves as a partial agonist.
Asunto(s)
Piridinas/síntesis química , Piridinas/farmacología , Receptores de Serotonina/química , Receptores de Serotonina/metabolismo , Tiazoles/síntesis química , Tiazoles/farmacología , Células Cultivadas , Humanos , Ligandos , Serotonina/metabolismo , Agonistas de Receptores de Serotonina/química , Agonistas de Receptores de Serotonina/farmacología , Relación Estructura-Actividad , beta-Lactamasas/metabolismoRESUMEN
Novel (E)-N(1)-(benzyl)cinnamamidines were prepared and evaluated as NR2B subtype NMDA receptor ligands. Excellent affinity was achieved by appropriate substitution of either phenyl ring. The 2-methoxybenzyl compound 1h had approximately 1,000-fold lower IC(50) in NR2B than NR2A-containing cells. Replacement of the styryl unit by 2-naphthyl was well tolerated.
Asunto(s)
Amidinas/síntesis química , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Amidinas/metabolismo , Benzamidinas/síntesis química , Benzamidinas/metabolismo , Evaluación Preclínica de Medicamentos , Humanos , Naftalenos/síntesis química , Naftalenos/metabolismo , Unión Proteica , Ensayo de Unión Radioligante , Receptores de N-Metil-D-Aspartato/metabolismo , Relación Estructura-ActividadRESUMEN
A novel series of benzamidines was synthesized and shown to exhibit NR2B-subtype selective NMDA antagonist activity. Compound 31 is orally active in a carrageenan-induced rat hyperalgesia model of pain and shows no motor coordination side effects.