RESUMO
A series of fused cyclopropyl-4,5-dihydropyridazin-3-one (3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one) phenoxypiperidine analogs was designed and synthesized, leading to the identification of (1R,6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (R,S-4a) as a second-generation pyridazin-3-one H3R antagonist. Compound R,S-4a was a potent H3R functional antagonist in vivo in the rat dipsogenia model, demonstrated potent wake activity in the rat EEG/EMG model, and enhanced short-term memory in the rat social recognition memory model at doses as low as 0.03-0.3 mg/kg po.
Assuntos
Nootrópicos/química , Piperidinas/química , Piridazinas/química , Receptores Histamínicos H3/química , Animais , Transtornos Cognitivos/tratamento farmacológico , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Agonismo Inverso de Drogas , Meia-Vida , Haplorrinos , Memória de Curto Prazo/efeitos dos fármacos , Nootrópicos/farmacocinética , Nootrópicos/farmacologia , Nootrópicos/uso terapêutico , Piperidinas/farmacocinética , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Piridazinas/farmacocinética , Piridazinas/farmacologia , Piridazinas/uso terapêutico , Ratos , Receptores Histamínicos H3/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel class of benzocinnolinones analogs of irdabisant were designed and synthesized as histamine H3R antagonists/inverse agonists. Modifications to the pyridazinone portion of the core and linker led to the identification of molecules with excellent target potency and selectivity with improved rat pharmacokinetic properties and reduced potential hERG liabilities.
Assuntos
Compostos Heterocíclicos com 3 Anéis/síntese química , Agonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos H3/síntese química , Nootrópicos/síntese química , Piridazinas/síntese química , Pirrolidinas/síntese química , Receptores Histamínicos H3/química , Animais , Células CHO , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Cricetinae , Relação Dose-Resposta a Droga , Agonismo Inverso de Drogas , Compostos Heterocíclicos com 3 Anéis/farmacologia , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Estrutura Molecular , Nootrópicos/farmacologia , Piridazinas/farmacologia , Pirrolidinas/farmacologia , Ratos , Receptores Histamínicos H3/metabolismo , 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
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.
Assuntos
Ingestão de Líquidos/efeitos dos fármacos , Agonistas dos Receptores Histamínicos/farmacologia , Piridazinas/farmacologia , Vigília/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Agonistas dos Receptores Histamínicos/síntese química , Agonistas dos Receptores Histamínicos/química , Humanos , Masculino , Estrutura Molecular , Piridazinas/síntese química , Piridazinas/química , Ratos , Receptores Histamínicos H3/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The optimization of the dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-one R(2) and R(12) positions led to the identification of the first MLK1 and MLK3 subtype-selective inhibitors within the MLK family. Compounds 14 (CEP-5104) and 16 (CEP-6331) displayed good potency for MLK1 and MLK3 inhibition with a greater than 30- to 100-fold selectivity for related family members MLK2 and DLK. Compounds 14 and 16 were orally active in vivo in a mouse MPTP biochemical efficacy model that was comparable to the first-generation pan-MLK inhibitor 1 (CEP-1347). The MLK1 structure-activity relationships were supported by the first-reported X-ray crystal structure of MLK1 bound with 16.