RESUMEN
Optimization of the amino acid residue within a series of anthranilimide-based glycogen phosphorylase inhibitors is described. These studies culminated in the identification of anthranilimides 16 and 22 which displayed potent in vitro inhibition of GPa in addition to reduced inhibition of CYP2C9 and excellent pharmacokinetic properties.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas/antagonistas & inhibidores , Ácidos Carboxílicos/química , Química Farmacéutica/métodos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucógeno Fosforilasa/antagonistas & inhibidores , Imidas/farmacología , ortoaminobenzoatos/farmacología , Animales , Hidrocarburo de Aril Hidroxilasas/química , Cristalografía por Rayos X , Citocromo P-450 CYP2C9 , Perros , Diseño de Fármacos , Glicina/química , Glucógeno Fosforilasa/metabolismo , Humanos , Imidas/química , Concentración 50 Inhibidora , Hígado/enzimología , Conformación Molecular , Ratas , ortoaminobenzoatos/químicaRESUMEN
A series of tetrahydrobenzofuranyl and tetrahydrobenzothienyl propenoic acids that showed potent agonist activity against RXRalpha were synthesized via a structure-based design approach. Among the compounds studied, 46a,b showed not only very good potency against RXRalpha (K(i) = 6 nM) but was also found to be greater than 167-fold selective vs RARalpha (K(i) > 1000 nM). This compound profiled out as a full agonist in a cell-based transient transfection assay (EC(50) = 3 nM). The two antipodes were separated via chiral chromatography, and 46b was found to be 40-fold more potent than 46a. Interestingly, cocrystallization of 46a,b with the RXRalpha protein generated a liganded structure whereby the (S)-antipode was found in the binding pocket. Given orally in db/db mice or ZDF rats, 46a,b showed a significant glucose-lowering effect and an increase in liver mass. Triglycerides decreased significantly in db/db mice but increased in the ZDF rats. A dose-dependent decrease of nonesterified free fatty acids was seen in ZDF rats but not in db/db mice. These differences indicate a species specific effect of RXR agonists on lipid metabolism.
Asunto(s)
Acrilatos/síntesis química , Benzofuranos/síntesis química , Hipoglucemiantes/síntesis química , Receptores de Ácido Retinoico/agonistas , Factores de Transcripción/agonistas , Acrilatos/química , Acrilatos/farmacología , Animales , Benzofuranos/química , Benzofuranos/farmacología , Sitios de Unión , Línea Celular , Cristalografía por Rayos X , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Haplorrinos , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Ligandos , Lípidos/biosíntesis , Masculino , Ratones , Modelos Moleculares , Ensayo de Unión Radioligante , Ratas , Ratas Zucker , Receptores de Ácido Retinoico/química , Receptores de Ácido Retinoico/genética , Receptores X Retinoide , Estereoisomerismo , Relación Estructura-Actividad , Factores de Transcripción/química , Factores de Transcripción/genética , TransfecciónRESUMEN
The first report on the identification and structure-activity relationships of a novel series of GPR40 agonists based on a 3-(4-{[N-alkyl]amino}phenyl)propanoic acid template is described. Structural modifications to the original screening hit yielded compounds with a 100-fold increase in potency at the human GPR40 receptor and pEC(50)s in the low nanomolar range. The carboxylic acid moiety is not critical for activity but typically elicits an agonistic response higher than those observed with carboxamide replacements. These compounds may prove useful in unraveling the therapeutic potential of this receptor for the treatment of Type 2 diabetes.