RESUMO
In an effort to discover novel CRF-1 receptor antagonists exhibiting improved physicochemical properties, a dihydropirrole[2,3]pyridine scaffold was designed and explored in terms of the SAR of the substitution at the pendent phenyl ring and the nature of the heterocyclic moieties present in the upper region of the molecule. Selective and potent compounds have been discovered endowed with reduced ClogP with respect to compounds known in the literature. Of particular relevance was the finding that the in vitro affinity of the series was maintained by reducing the overall lipophilicity. The results achieved by this exploration enabled the formulation of a novel hypothesis on the nature of the receptor binding pocket of this class of CRF-1 receptor antagonists, making use of in silico docking studies of the putative nonpeptidic antagonist binding site set up in house by homology modeling techniques.
Assuntos
Simulação por Computador , Piridinas/farmacologia , Pirróis/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Sítios de Ligação , Células CHO , Cricetinae , Cricetulus , Desenho de Fármacos , Ligantes , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Pirróis/síntese química , Pirróis/química , Relação Quantitativa Estrutura-Atividade , EstereoisomerismoRESUMO
To identify new CRF(1) receptor antagonists, an attempt to modify the bis-heterocycle moiety present in the top region of the dihydropyrrole[2,3]pyridine template was made following new pharmacophoric hypothesis on the CRF(1) receptor antagonists binding pocket. In particular, the 2-thiazole ring, present in the previous series of compounds, was replaced by more hydrophilic non aromatic heterocycles able to make appropriate H-bond interactions with amino acid residues Thr192 and Tyr195. This exploration, followed by an accurate analysis of the substitution of the pendant aryl ring, enabled to identify in vitro potent compounds showing excellent pharmacokinetics and outstanding in vivo activity in animal models of anxiety, both in rodents and primates.
Assuntos
Piridinas/síntese química , Piridinas/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Feminino , Membro Anterior/efeitos dos fármacos , Gerbillinae , Humanos , Masculino , Modelos Químicos , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Testes Psicológicos , Piridinas/química , Pirróis/química , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Ultrassom , Vocalização Animal/efeitos dos fármacosRESUMO
The synthesis of a series of carbazole derivatives and their SAR at the NPY Y1 receptor is described. Modulation of physicochemical properties by appropriate decoration led to the identification of a high-affinity NPY Y1 antagonist that shows high brain penetration and modest oral bioavailability.
Assuntos
Carbazóis/síntese química , Carbazóis/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Animais , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células CHO , Carbazóis/farmacocinética , Fenômenos Químicos , Físico-Química , Cricetinae , Cricetulus , Meia-Vida , Indicadores e Reagentes , Masculino , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
The SAR of a new series of tetrahydrocarbazole derivatives is described: the appropriate decoration of this template led to the identification of a new class of NPY-1 antagonists showing good in vitro potency and a promising in vivo pharmacokinetic profile in rat.