RESUMEN

Spiroindoline urea derivatives, designed to act as NPY Y5 receptor antagonists, were synthesized and their structure-activity relationships were investigated. Of these derivatives, compound 3a showed good Y5 binding affinity with favorable pharmacokinetic properties. Compound 3a significantly inhibited bPP Y5 agonist-induced food intake in rats, and suppressed body weight gain in DIO mice.

Asunto(s)

Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Indoles/química , Indoles/farmacología , Receptores de Neuropéptido Y/antagonistas & inhibidores , Receptores de Neuropéptido Y/metabolismo , Animales , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacocinética , Disponibilidad Biológica , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Indoles/síntesis química , Indoles/farmacocinética , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Unión Proteica , Ratas , Ratas Sprague-Dawley , Receptores de Neuropéptido Y/agonistas , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Relación Estructura-Actividad

RESUMEN

A series of novel imidazoline derivatives was synthesized and evaluated as neuropeptide Y (NPY) Y5 receptor antagonists. Optimization of previously reported imidazoline leads, 1a and 1b, was attempted by introduction of substituents at the 5-position on the imidazoline ring and modification of the bis(4-fluorphenyl) moiety. A number of potent derivatives without human ether-a-go-go related gene potassium channel (hERG) activity were identified. Selected compounds, including 2a, were shown to have excellent brain and CSF permeability. Compound 2a displayed a suitable pharmacokinetic profile for chronic in vivo studies and potently inhibited D-Trp(34)NPY-induced acute food intake in rats. Oral administration of 2a resulted in a potent reduction of body weight in a diet-induced obese mouse model.

Asunto(s)

Fármacos Antiobesidad/química , Canales de Potasio Éter-A-Go-Go/metabolismo , Imidazolinas/farmacología , Obesidad/tratamiento farmacológico , Receptores de Neuropéptido Y/antagonistas & inhibidores , Animales , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacología , Encéfalo/metabolismo , Líquido Cefalorraquídeo/metabolismo , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Canal de Potasio ERG1 , Humanos , Imidazolinas/síntesis química , Imidazolinas/química , Farmacocinética , Unión Proteica/efectos de los fármacos , Ratas , Relación Estructura-Actividad , Pérdida de Peso/efectos de los fármacos

RESUMEN

Novel imidazoline derivatives were discovered to be potent neuropeptide Y Y5 receptor antagonists. High-throughput screening of Merck sample collections against the human Y5 receptor resulted in the identification of 2,4,4-triphenylimidazoline (1), which had an IC(50) of 54nM. Subsequent optimization led to the identification of several potent derivatives.

Asunto(s)

Química Farmacéutica/métodos , Imidazoles/química , Receptores de Neuropéptido Y/química , Animales , Encéfalo/metabolismo , Ácidos Carboxílicos/química , Líquido Cefalorraquídeo/metabolismo , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Ratones , Modelos Químicos , Estructura Molecular , Relación Estructura-Actividad

RESUMEN

Reaction of 3-butenyl radicals generated by photolysis of variously substituted Barton esters (both open-chain 1a-d and cyclohexyl 1e-h) with CF(2)=CCl(2) gave a mixture of cyclized products (cyclopentanes 6 and 8 and cyclohexanes 7 and 9) as well as noncyclized products (4and 5) in various ratios depending on the substitution pattern at the olefinic moiety. The product ratios of [cyclization (6 + 7 + 8 + 9):noncyclization (5)] for 1 with more alkyl substituents on the CC double bond were greater than those for 1 with fewer substituents. The products ratio of [5-exo (6 + 8):6-endo (7 + 9)] was influenced by a steric effect. Photoreaction of Barton ester 2 with CF(2)=CCl(2) gave a mixture of cyclohexanes 16 and 17 as well as noncyclized 14 and 15. Dehydrochlorination of decalins 7g and 7h followed by oxidation of sulfide and [2,3]sigmatropic rearrangement of the allyl sulfoxide gave octahydronaphthalenones 23 and 27, respectively.