Assuntos
Dibenzocicloeptenos/síntese química , Dibenzocicloeptenos/farmacologia , Hipnóticos e Sedativos/síntese química , Ciclização , Dibenzocicloeptenos/química , Humanos , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/farmacologia , Mianserina/análogos & derivados , Mianserina/química , Mianserina/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
Histamine H(1) and serotonin 5-HT(2A) receptors mediate two different mechanisms involved in sleep regulation: H(1) antagonists are sleep inducers, while 5-HT(2A) antagonists are sleep maintainers. Starting from 9'a, a novel spirotetracyclic compound endowed with good H(1)/5-HT(2A) potency but poor selectivity, very high Cli, and a poor P450 profile, a specific optimization strategy was set up. In particular, we investigated the possibility of introducing appropriate amino acid moieties to optimize the developability profile of the series. Following this zwitterionic approach, we were able to identify several advanced leads (51, 65, and 73) with potent dual H(1)/5-HT(2A) activity and appropriate developability profiles. These compounds exhibited efficacy as hypnotic agents in a rat telemetric sleep model with minimal effective doses in the range 3-10 mg/kg po.
Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Antagonistas dos Receptores Histamínicos H1/síntese química , Hipnóticos e Sedativos/síntese química , Receptor 5-HT2A de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/síntese química , Sono/efeitos dos fármacos , Compostos de Espiro/síntese química , Animais , Disponibilidade Biológica , Encéfalo/metabolismo , Linhagem Celular , Córtex Cerebral/metabolismo , Cricetinae , Cricetulus , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Antagonistas dos Receptores Histamínicos H1/química , Antagonistas dos Receptores Histamínicos H1/farmacologia , Humanos , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/farmacologia , Masculino , Microssomos Hepáticos/metabolismo , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Antagonistas do Receptor 5-HT2 de Serotonina/química , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Transtornos do Sono-Vigília/tratamento farmacológico , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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 fármacosAssuntos
Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Desenho de Fármacos , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Ansiedade/patologia , Hormônio Liberador da Corticotropina/metabolismo , Depressão/patologia , Modelos Químicos , Pirazóis/síntese química , Pirazóis/farmacocinética , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
Two new classes of potent and selective CRF(1) receptor antagonists are presented. Exploration of general templates 3 and 4 through modifications of the top amine and bottom phenyl substituents led to optimization of the in vitro affinity and pharmacokinetic profiles. The typical alkyl chains present in the top region of CRF(1) antagonists were replaced by substituted heteroaryl moieties, leading to a dramatic improvement of the metabolic stability. This improvement was apparent when the compounds were dosed in vivo: several compounds exhibited low plasma clearance, good oral bioavailability, and high brain penetration. As a consequence of their outstanding pharmacokinetic profiles, these CRF(1) antagonists, as exemplified by compound 4 fi (4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-7-(2,4-dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine), produced a dose-dependent "anxiolytic-like" effect when administered orally, decreasing the vocalization of rat pups.