RESUMEN
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.
Asunto(s)
Morfolinas/síntesis química , Quinoxalinas/síntesis química , Receptor de Colecistoquinina B/antagonistas & inhibidores , Sulfonamidas/síntesis química , ortoaminobenzoatos/síntesis química , Animales , Unión Competitiva , Disponibilidad Biológica , Perros , Estabilidad de Medicamentos , Vesícula Biliar/efectos de los fármacos , Vesícula Biliar/fisiología , Ácido Gástrico/metabolismo , Cobayas , Humanos , Técnicas In Vitro , Masculino , Microsomas Hepáticos/metabolismo , Morfolinas/química , Morfolinas/farmacología , Contracción Muscular , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Quinoxalinas/química , Quinoxalinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptor de Colecistoquinina A/antagonistas & inhibidores , Estereoisomerismo , Estómago/efectos de los fármacos , Estómago/fisiología , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacologíaRESUMEN
Orexins, also termed hypocretins, consist of two neuropeptide agonists (orexin A and B) interacting with two known G-protein coupled receptors (OX(1)R and OX(2)R). In addition to other biological functions, the orexin-2 receptor is thought to be an important modulator of sleep and wakefulness. Herein we describe a series of novel, selective OX(2)R antagonists consisting of substituted 4-phenyl-[1,3]dioxanes. One such antagonist is compound 9, 1-(2,4-dibromo-phenyl)-3-((4S,5S)-2,2-dimethyl-4-phenyl-[1,3]dioxan-5-yl)-urea, which is bound by the OX(2)R with a pK(i) of 8.3, has a pK(b) of 7.9, and is 600-fold selective for the OX(2)R over the OX(1)R.