RESUMEN
Previous research on histamine H(3) antagonists has led to the development of a pharmacophore model consisting of a central phenyl core flanked by two alkylamine groups. Recent investigation of the replacement of the central phenyl core with heteroaromatic fragments resulted in the preparation of novel 3,5-, 3,6- and 3,7-substituted indole and 3,5-substituted benzothiophene analogs that demonstrate good to excellent hH(3) affinities. Select analogs were profiled in a rat pharmacokinetic model.
Asunto(s)
Antagonistas de los Receptores Histamínicos H3/síntesis química , Antagonistas de los Receptores Histamínicos H3/farmacología , Indoles/síntesis química , Indoles/farmacología , Tiofenos/síntesis química , Tiofenos/farmacología , Animales , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Indicadores y Reactivos , Indoles/farmacocinética , Isomerismo , Modelos Moleculares , Ratas , Relación Estructura-Actividad , Tiofenos/farmacocinéticaRESUMEN
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.
Asunto(s)
Isoxazoles/química , Receptor de Colecistoquinina A/antagonistas & inhibidores , Receptor de Colecistoquinina B/antagonistas & inhibidores , Sulfonamidas/farmacología , Animales , Benzamidas/farmacología , Clonación Molecular , Evaluación Preclínica de Medicamentos , Genotipo , Aprendizaje por Laberinto , Modelos Moleculares , Ratas , Ratas Sprague-Dawley , Receptor de Colecistoquinina A/genética , Receptor de Colecistoquinina A/metabolismo , Receptor de Colecistoquinina B/genética , Receptor de Colecistoquinina B/metabolismo , Relación Estructura-ActividadRESUMEN
A novel series of cholecystokinin-2 receptor (CCK-2R) antagonists has been identified, as exemplified by anthranilic sulfonamide 1 (pK(i)=7.6). Pharmacokinetic and stability studies indicated that this series of compounds suffered from metabolic degradation, and that both the benzothiadiazole and piperidine rings were rapidly oxidized by liver enzymes. A combination of synthesis, computational methods, (1)H NMR conformational studies, and X-ray crystallographic analyses were applied to elucidate key pharmacophore elements, and to discover analogs with improved pharmacokinetic profiles, and high receptor binding affinity and selectivity.
Asunto(s)
Receptor de Colecistoquinina B/antagonistas & inhibidores , Animales , Benzotiazoles/síntesis química , Benzotiazoles/química , Benzotiazoles/farmacología , Cristalografía por Rayos X , Humanos , Espectroscopía de Resonancia Magnética , Microsomas Hepáticos/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Receptor de Colecistoquinina A/metabolismo , Receptor de Colecistoquinina B/metabolismo , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
A novel strategy for the synthesis of cholecystokinin-2 receptor ligands was developed. The route employs a solution-phase synthesis of a series of anthranilic sulfonamides followed by a resin capture purification strategy to produce multi-milligram quantities of compounds for bioassay. The synthesis was used to produce >100 compounds containing various functional groups, highlighting the general applicability of this strategy and to address specific metabolism issues in our CCK-2 program.
Asunto(s)
Colecistoquinina/metabolismo , Técnicas Químicas Combinatorias , Receptor de Colecistoquinina B/metabolismo , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , ortoaminobenzoatos/síntesis química , ortoaminobenzoatos/farmacología , Animales , Diseño de Fármacos , Humanos , Ligandos , Microsomas Hepáticos/efectos de los fármacos , Estructura Molecular , Ratas , Relación Estructura-Actividad , Sulfonamidas/química , ortoaminobenzoatos/químicaRESUMEN
Development of a scalable synthesis of an oxazine class of ß-secretase inhibitor is described. Trifluoromethylated acyloin synthesis by the reaction of a mandelic acid with trifluoroacetic anhydride in the presence of pyridine (Dakin-West reaction) was used as an efficient strategy to install the key trifluoromethyl substituent on the oxazine ring. Diastereoselective addition of methyl magnesium bromide to a cyclic sulfamidate imine and trimethylsilyl trifluoromethanesulfonate catalyzed intramolecular amidine formation to yield oxazine-3-amine are some of the significant, novel synthetic methods developed in this synthesis. These critical transformations allowed a concise 11-step route to the target compound with excellent overall yields.
RESUMEN
The synthesis and preclinical characterization of novel 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are potent and selective brain penetrant P2X7 antagonists are described. Optimization efforts based on previously disclosed unsubstituted 6,7-dihydro-4H-triazolo[4,5-c]pyridines, methyl substituted 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazines, and several other series lead to the identification of a series of 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are selective P2X7 antagonists with potency at the rodent and human P2X7 ion channels. These novel P2X7 antagonists have suitable physicochemical properties, and several analogs have an excellent pharmacokinetic profile, good partitioning into the CNS and show robust in vivo target engagement after oral dosing. Improvements in metabolic stability led to the identification of JNJ-54175446 (14) as a candidate for clinical development. The drug discovery efforts and strategies that resulted in the identification of the clinical candidate are described herein.
Asunto(s)
Antagonistas del Receptor Purinérgico P2X/farmacología , Piridinas/farmacología , Receptores Purinérgicos P2X7/efectos de los fármacos , Animales , Disponibilidad Biológica , Humanos , Antagonistas del Receptor Purinérgico P2X/farmacocinéticaRESUMEN
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
We have previously reported a novel class of tetrahydroindazoles that display potency against a variety of Gram-positive and Gram-negative bacteria, potentially via interaction with type II bacterial topoisomerases. Herein are reported SAR investigations of this new series. Several compounds possessing broad-spectrum potency were prepared. Further, these compounds exhibit activity against multidrug-resistant Gram-positive microorganisms equivalent to that against susceptible strains.