RESUMEN
The design and development of a series of highly selective pyrrolidine carboxamide 11beta-HSD1 inhibitors are described. These compounds including PF-877423 demonstrated potent in vitro activity against both human and mouse 11beta-HSD1 enzymes. In an in vivo assay, PF-877423 inhibited the conversion of cortisone to cortisol. Structure guided optimization effort yielded potent and stable 11beta-HSD1 selective inhibitor 42.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/análogos & derivados , Amidas/química , Inhibidores Enzimáticos/química , Hipoglucemiantes/química , Pirrolidinas/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Adamantano/síntesis química , Adamantano/química , Adamantano/farmacología , Amidas/síntesis química , Amidas/farmacología , Animales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Cobayas , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , Ratones , Microsomas Hepáticos/metabolismo , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Relación Estructura-ActividadRESUMEN
Analogues substituted with various amines at the 6-position of the pyrazine ring on (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrazin-2-ylmethanone were discovered as potent and selective inhibitors of PDK1 with potential as anticancer agents. An early lead with 2-pyridine-3-ylethylamine as the pyrazine substituent showed moderate potency and selectivity. Structure-based drug design led to improved potency and selectivity against PI3Kα through a combination of cyclizing the ethylene spacer into a saturated, five-membered ring and substituting on the 4-position of the aryl ring with a fluorine. ADME properties were improved by lowering the lipophilicity with heteroatom replacements in the saturated, five-membered ring. The optimized analogues have a PDK1 Ki of 1 nM and >100-fold selectivity against PI3K/AKT-pathway kinases. The cellular potency of these analogues was assessed by the inhibition of AKT phosphorylation (T308) and by their antiproliferation activity against a number of tumor cell lines.