RESUMO
Novel, achiral 1H-1,3,5-benzotriazepine-2,4(3H,5H)-diones have been prepared and structurally characterized. These compounds are potent CCK(2) receptor antagonists that display a high degree of selectivity over CCK(1) receptors.
Assuntos
Receptor de Colecistocinina B/antagonistas & inibidores , Triazinas/química , Triazinas/farmacologia , Animais , Benzazepinas/química , Benzazepinas/farmacologia , Humanos , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
A 1,3,4-benzotriazepine was identified as a suitable lead in our effort toward obtaining a non-peptide parathyroid hormone-1 receptor (PTH1R) antagonist. A process of optimization afforded derivatives displaying nanomolar PTH1R affinity, a representative example of which behaved as a PTH1R antagonist in cell-based cyclic adenosine monophosphate (cAMP) assays, with selectivity over PTH2 receptors.
Assuntos
Benzazepinas/síntese química , Receptor Tipo 1 de Hormônio Paratireóideo/antagonistas & inibidores , Animais , Benzazepinas/química , Benzazepinas/farmacologia , Ligação Competitiva , Linhagem Celular , Linhagem Celular Tumoral , Cricetinae , Cricetulus , AMP Cíclico/biossíntese , Humanos , Camundongos , Ensaio Radioligante , Proteínas Recombinantes/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
The systematic optimization of the structure of a novel 2,4,5-trisubstituted imidazole-based cholecystokinin-2 (CCK(2)) receptor antagonist afforded analogues with nanomolar receptor affinity. These compounds were now comparable in their potency to the bicyclic heteroaromatic-based compounds 5 (JB93182) and 6 (JB95008), from which the initial examples were designed using a field-point based molecular modeling approach. They were also orally active as judged by their inhibition of pentagastrin stimulated acid secretion in conscious dogs, in contrast to the bicyclic heteroaromatic-based compounds, which were ineffective because of biliary elimination. Increasing the hydrophilicity through replacement of a particular methylene group with an ether oxygen, as in 3-{[5-(adamantan-1-yloxymethyl)-2-cyclohexyl-1H-imidazole-4-carbonyl]amino}benzoic acid (53), had little effect on the receptor affinity but significantly increased the oral potency. Comparison of the plasma pharmacokinetics and the inhibition of pentagastrin-stimulated acid output following bolus intraduodenal administration of both 53 and 6 indicated that 53 was well absorbed, had a longer half-life, and was not subject to the elimination pathways of the earlier series.
