RESUMO
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.
Assuntos
Compostos de Anilina/química , Compostos de Anilina/uso terapêutico , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Reação de Arthus/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/química , Pirimidinas/uso terapêutico , Administração Oral , Compostos de Anilina/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Cristalografia por Raios X , Descoberta de Drogas , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Modelos Moleculares , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/farmacologia , Ratos , Relação Estrutura-Atividade , Quinase SykRESUMO
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.
Assuntos
Alcinos/síntese química , Éteres Cíclicos/síntese química , Alcinos/química , Cristalografia por Raios X , Éteres Cíclicos/química , Modelos Moleculares , Conformação Molecular , EstereoisomerismoRESUMO
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.
Assuntos
Piridinas/síntese química , Piridinas/farmacologia , Receptores de Serotonina/química , Receptores de Serotonina/metabolismo , Tiazóis/síntese química , Tiazóis/farmacologia , Células Cultivadas , Humanos , Ligantes , Serotonina/metabolismo , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/farmacologia , Relação Estrutura-Atividade , beta-Lactamases/metabolismoRESUMO
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.
Assuntos
Amidinas/síntese química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Amidinas/metabolismo , Benzamidinas/síntese química , Benzamidinas/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Naftalenos/síntese química , Naftalenos/metabolismo , Ligação Proteica , Ensaio Radioligante , Receptores de N-Metil-D-Aspartato/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
