RESUMO
We describe a practical and scalable route to compound (Z)-1, a selective CCK1 receptor antagonist. Notable features of this concise route are (1) a regioselective construction of the pyrazole core through the reaction of an aryl hydrazine and an elaborated acetylenic ketone, (2) a Tf2O/pyridine mediated Z-selective dehydration of an α-hydroxyester, and (3) a stereoselective hydrolysis. The sequence is high-yielding and amenable for large-scale synthesis.
Assuntos
Clorobenzenos/síntese química , Dioxóis/síntese química , Dioxóis/farmacologia , Hidrazinas/química , Propionatos/síntese química , Pirazóis/química , Pirazóis/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Clorobenzenos/química , Dioxóis/química , Hidrólise , Cetonas/química , Estrutura Molecular , Propionatos/química , Pirazóis/síntese química , EstereoisomerismoRESUMO
A series of CCK2R-selective anthranilic amides is shown to derive CCK1R affinity via selective substitution of the amide side chain. Thus, extending the length of the original benzamide side chain by a single methylene unit imparts CCK1R affinity to the series, and further fine tuning of the affinity results in CCK1R selectivity of greater than 100-fold.
Assuntos
Isoxazóis/química , Receptor de Colecistocinina A/antagonistas & inibidores , Receptor de Colecistocinina B/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Benzamidas/farmacologia , Clonagem Molecular , Avaliação Pré-Clínica de Medicamentos , Genótipo , Aprendizagem em Labirinto , Modelos Moleculares , Ratos , Ratos Sprague-Dawley , Receptor de Colecistocinina A/genética , Receptor de Colecistocinina A/metabolismo , Receptor de Colecistocinina B/genética , Receptor de Colecistocinina B/metabolismo , Relação Estrutura-AtividadeRESUMO
In the previous article we demonstrated how certain CCK2R-selective anthranilic amides could be structurally modified to afford high-affinity, selective CCK1R activity. We now describe our efforts at modulating and optimizing the CCK1R and CCK2R affinities aimed at producing compounds with good pharmacokinetics properties and in vivo efficacy in rat models of gastric acid and pancreatic amylase secretion.
Assuntos
Isoxazóis/química , Receptor de Colecistocinina A/antagonistas & inibidores , Receptor de Colecistocinina B/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Substituição de Aminoácidos , Animais , Modelos Moleculares , Ratos , Ratos Wistar , Resultado do TratamentoRESUMO
A high throughput screening approach to the identification of selective cholecystokinin-2 receptor (CCK-2R) ligands resulted in the discovery of a novel series of antagonists, represented by 1-[2-[(2,1,3-benzothiadiazol-4-ylsulfonyl)amino]-5-chlorobenzoyl]-piperidine (1; CCK-2R, pK(I) = 6.4). Preliminary exploration of the structure-activity relationships around the anthranilic ring and the amide and sulfonamide moieties led to a nearly 50-fold improvement of receptor affinity and showed a greater than 1000-fold selectivity over the related cholecystokinin-1 receptor. Pharmacokinetic evaluation led to the identification of 4-[4-iodo-2-[(5-quinoxalinylsulfonyl)amino]benzoyl]-morpholine, 26d, a compound that demonstrates promising pharmacokinetic properties in the rat and dog with respect to plasma clearance and oral bioavailability and is a potent inhibitor in vivo of pentagastrin-stimulated acid secretion in the rat when dosed orally.