RESUMO
Structure-activity relationship on a novel ketone class of H(3)R antagonists/inverse agonists is disclosed. Compound 4 showed excellent target potency, selectivity and brain penetration. Evaluation of antagonist 4 in the rat EEG/EMG model demonstrated robust wake activity thereby establishing preclinical proof of concept.
Assuntos
Agonistas dos Receptores Histamínicos/farmacologia , Cetonas/química , Morfolinas/química , Receptores Histamínicos H3 , Vigília/efeitos dos fármacos , Animais , Eletroencefalografia , Agonistas dos Receptores Histamínicos/química , Humanos , Cetonas/farmacologia , Masculino , Estrutura Molecular , Morfolinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
7-Arylsulfonyl substituted benzofuropiperidine was discovered as a novel scaffold for 5HT(6) receptor antagonists. Optimization by substitution at C-1 position led to identification of selective, orally bioavailable, brain penetrant antagonists with reduced hERG liability. An advanced analog tested in rat social recognition model showed significant activity suggesting potential utility in the enhancement of short-term memory.
Assuntos
Benzofuranos/química , Piperidinas/química , Receptores de Serotonina/química , Antagonistas da Serotonina/farmacologia , Animais , Encéfalo/embriologia , Encéfalo/metabolismo , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Concentração Inibidora 50 , Cinética , Memória de Curto Prazo/efeitos dos fármacos , Modelos Químicos , Ratos , Esquizofrenia/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
Pyridazinone 1 was recently reported as a potent H(3)R antagonist with good drug-like properties and in vivo activity. A series of constrained amine analogs of 1 was synthesized to identify compounds with improved pharmacokinetic profiles. From these efforts, a new class of (S)-2-pyrrolidin-1-ylmethyl-1-pyrrolidinyl amides was identified.
Assuntos
Aminas/química , Antagonistas dos Receptores Histamínicos H3/farmacologia , Piridazinas/farmacologia , Animais , Relação Dose-Resposta a Droga , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/química , Humanos , Estrutura Molecular , Piridazinas/síntese química , Piridazinas/química , Ratos , Receptores Histamínicos H3/metabolismo , Estereoisomerismo , 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.