RESUMEN
A novel modular synthetic approach toward constrained peptidomimetics is reported. The approach involves a highly efficient three-step sequence including two multicomponent reactions, thus allowing unprecedented diversification of both the peptide moieties and the turn-inducing scaffold. The turn-inducing properties of the dihydropyridone scaffold were evaluated by molecular modeling, X-ray crystallography, and NMR studies of a resulting peptidomimetic. Although modeling studies point toward a type IV beta-turn-like structure, the X-ray crystal structure and NMR studies indicate an open turn structure.
Asunto(s)
Materiales Biomiméticos/química , Conformación Molecular , Péptidos/química , Cristalografía por Rayos X , Espectroscopía de Resonancia Magnética , Modelos Moleculares , TemperaturaRESUMEN
The progesterone receptor plays an important role in the female reproductive system. Here we describe the discovery of a new selective progesterone receptor modulator (SPRM). In rats, the lead compound, 7,9-difluoro-5-(3-methylcyclohex-2-enyl)-2,2,4-trimethyl-1,2-dihydrochromeno[3,4- f]quinoline ( 5c), inhibited ovulation and showed full efficacy in uterine and vaginal tissue but was a mixed partial agonist/antagonist in breast tissue. The compound also suppressed ovulation in monkeys, but in contrast to currently approved steroidal PR agonists, it did not suppress estradiol levels.
Asunto(s)
Benzopiranos/síntesis química , Benzopiranos/farmacología , Quinolinas/síntesis química , Quinolinas/farmacología , Receptores de Progesterona/antagonistas & inhibidores , Animales , Benzopiranos/química , Femenino , Haplorrinos , Humanos , Estructura Molecular , Ovulación/efectos de los fármacos , Quinolinas/química , Ratas , Receptores de Progesterona/metabolismo , Relación Estructura-ActividadRESUMEN
The synthesis of 13,14-seco steroids starting from easily available (13S)-13-iodo-6beta-methoxy-3alpha,5-cyclo-13,14-seco-5alpha-androsta-14,17-dione is described. The C-17 ketone was converted regioselectively into its oxime with simultaneous stereoselective deiodination at C-13. The remaining C-14 carbonyl group was then reduced stereoselectively with Ca(BH4)2. The configurations at the relevant stereocenters of the thus obtained hydroxy oxime were determined by X-ray analysis. Successful regeneration of the C-17 carbonyl group was achieved by treatment of the corresponding oxime acetate with TiCl3.