RESUMO
A novel class of 1'-cyclobutyl-6-(4-piperidyloxy)spiro[benzopyran-2,4'-piperidine] derivatives with low nanomolar affinity for the human and rat histamine-3 receptors (H(3)Rs) are described. The spirobenzopyran piperidine ether analogs demonstrated excellent H(3)R affinity and selectivity against histamine receptor subtypes (H(1)R, H(2)R, and H(4)R), were stable in liver microsomes, and had selectivity against CYP P450 enzymes. Compounds 10, 13, 15, and 16 demonstrated high H(3)R affinity, in vitro liver microsomal stability, selectivity against CYP isoforms, moreover, these ether analogs exhibited acceptable iv pharmacokinetic (PK) properties but had poor oral exposure in rat.
Assuntos
Benzopiranos/síntese química , Antagonistas dos Receptores Histamínicos/síntese química , Piperidinas/síntese química , Receptores Histamínicos H3/metabolismo , Compostos de Espiro/síntese química , Administração Oral , Animais , Benzopiranos/farmacocinética , Benzopiranos/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Antagonistas dos Receptores Histamínicos/farmacocinética , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Injeções Intravenosas , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Piperidinas/farmacocinética , Piperidinas/farmacologia , Ratos , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
Structure-activity relationships for a series of phenoxypiperidine pyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. The search for compounds with improved hERG and DAT selectivity without the formation of in vivo active metabolites identified 6-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-4,4-dimethyl-4,5-dihydro-2H-pyridazin-3-one 17b. Compound 17b met discovery flow criteria, demonstrated potent H(3)R functional antagonism in vivo in the rat dipsogenia model and potent wake activity in the rat EEG/EMG model at doses as low as 0.1 mg/kg ip.
Assuntos
Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Piperidinas/química , Piridazinas/química , Receptores Histamínicos H3 , Vigília/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Modelos Moleculares , Estrutura Molecular , Piperidinas/farmacologia , Piridazinas/farmacologia , RatosRESUMO
H(3)R structure-activity relationships for a new class of 4,5-dihydropyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. Modification of the 4,5-dihydropyridazinone moiety to block in vivo metabolism identified 4,4-dimethyl-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-4,5-dihydro-2H-pyridazin-3-one 22 as a lead candidate demonstrating potent in vivo functional H(3)R antagonism in the rat dipsogenia model and robust wake promoting activity in the rat EEG/EMG model.
Assuntos
Agonistas dos Receptores Histamínicos/síntese química , Piridazinas/química , Receptores Histamínicos H3/química , Animais , Área Sob a Curva , Relação Dose-Resposta a Droga , Desenho de Fármacos , Eletroencefalografia/métodos , Eletromiografia/métodos , Agonistas dos Receptores Histamínicos/farmacologia , Cinética , Modelos Químicos , Piridazinas/síntese química , Piridazinas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Fatores de TempoRESUMO
A novel class of 4-alkoxy-[1'-cyclobutyl-spiro(3,4-dihydrobenzopyran-2,4'-piperidine)] analogues were designed and synthesized as H(3)R antagonists. Structure-activity relationship identified sulfone 27 with excellent H(3)R affinities in both humans and rats, and acceptable pharmacokinetic properties. Further, compound 28 achieved single digit nanomolar H(3)R affinities in both species with minimum hERG activity.
Assuntos
Antagonistas dos Receptores Histamínicos/química , Piperidinas/química , Receptores Histamínicos H3/química , Compostos de Espiro/síntese química , Animais , Química Farmacêutica/métodos , Desenho de Fármacos , Interações Medicamentosas , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Concentração Inibidora 50 , Cinética , Fígado/metabolismo , Camundongos , Modelos Químicos , Ratos , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of pyridazinone-phenethylamine derivatives with moderate to low nanomolar affinity for rat and human H(3)R are described. These analogs exhibited excellent selectivity and metabolic stability, with acceptable rat pharmacokinetic properties. In vivo, 7 and 11 demonstrated potent H(3)R functional antagonism in the rat dipsogenia model and robust wake-promoting activity in the rat electroencephalogram/electromyography (EEG/EMG) model.
Assuntos
Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Eletroencefalografia , Eletromiografia , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Humanos , Ratos , Relação Estrutura-AtividadeRESUMO
H(3)R structure-activity relationships on a novel class of pyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. Modifications of the pyridazinone core, central phenyl ring and linker led to the identification of molecules with excellent target potency, selectivity and pharmacokinetic properties. Compounds 13 and 21 displayed potent functional H(3)R antagonism in vivo in the rat dipsogenia model and demonstrated robust wake activity in the rat EEG/EMG model.
