RESUMO
Previous research on histamine H(3) antagonists has led to the development of a pharmacophore model consisting of a central phenyl core flanked by two alkylamine groups. Recent investigation of the replacement of the central phenyl core with heteroaromatic fragments resulted in the preparation of novel 3,5-, 3,6- and 3,7-substituted indole and 3,5-substituted benzothiophene analogs that demonstrate good to excellent hH(3) affinities. Select analogs were profiled in a rat pharmacokinetic model.
Assuntos
Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/farmacologia , Indóis/síntese química , Indóis/farmacologia , Tiofenos/síntese química , Tiofenos/farmacologia , Animais , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Indicadores e Reagentes , Indóis/farmacocinética , Isomerismo , Modelos Moleculares , Ratos , Relação Estrutura-Atividade , Tiofenos/farmacocinéticaRESUMO
The pre-clinical characterization of novel aryloxypyridine amides that are histamine H(3) receptor antagonists is described. These compounds are high affinity histamine H(3) ligands that penetrate the CNS and occupy the histamine H(3) receptor in rat brain. Several compounds were extensively profiled pre-clinically leading to the identification of two compounds suitable for nomination as development candidates.
Assuntos
Azepinas/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Piridinas/farmacologia , Amidas/química , Animais , Azepinas/química , Avaliação Pré-Clínica de Medicamentos , Piridinas/química , RatosRESUMO
Pre-clinical characterization of novel substituted pyrrolidines that are high affinity histamine H(3) receptor antagonists is described. These compounds efficiently penetrate the CNS and occupy the histamine H(3) receptor in rat brain following oral administration. One compound, (2S,4R)-1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, was extensively profiled and shows promise as a potential clinical candidate.
Assuntos
Azepinas/química , Antagonistas dos Receptores Histamínicos H3/química , Pirrolidinas/química , Receptores Histamínicos H3/química , Administração Oral , Animais , Azepinas/síntese química , Azepinas/farmacocinética , Encéfalo/metabolismo , Cães , Avaliação Pré-Clínica de Medicamentos , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Humanos , Camundongos , Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Ratos , Receptores Histamínicos H3/metabolismo , Relação Estrutura-AtividadeRESUMO
The preclinical characterization of novel phenyl(piperazin-1-yl)methanones that are histamine H3 receptor antagonists is described. The compounds described are high affinity histamine H3 antagonists. Optimization of the physical properties of these histamine H3 antagonists led to the discovery of several promising lead compounds, and extensive preclinical profiling aided in the identification of compounds with optimal duration of action for wake promoting activity. This led to the discovery of two development candidates for Phase I and Phase II clinical trials.
RESUMO
The synthesis and preclinical characterization of two novel, brain penetrating P2X7 compounds will be described. Both compounds are shown to be high potency P2X7 antagonists in human, rat, and mouse cell lines and both were shown to have high brain concentrations and robust receptor occupancy in rat. Compound 7 is of particular interest as a probe compound for the preclinical assessment of P2X7 blockade in animal models of neuro-inflammation.