Structure guided optimization of a series of nonpeptidic alkyl amine renin inhibitors allowed the rational incorporation of additional polar functionality. Replacement of the cyclohexylmethyl group occupying the S1 pocket with a (R)-(tetrahydropyran-3-yl)methyl group and utilization of a different attachment point led to the identification of clinical candidate 9. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans.

Structure-based design led to the discovery of a novel class of renin inhibitors in which an unprecedented phenyl ring filling the S1 site is attached to the phenyl ring filling the S3 pocket. Optimization for several parameters including potency in the presence of human plasma, selectivity against CYP3A4 inhibition and improved rat oral bioavailability led to the identification of 8d which demonstrated antihypertensive efficacy in a transgenic rat model of human hypertension.

Structure-guided drug design led to the identification of a class of spirocyclic ureas which potently inhibit human 11β-HSD1 in vitro. Lead compound 10j was shown to be orally bioavailable in three species, distributed into adipose tissue in the mouse, and its (R) isomer 10j2 was efficacious in a primate pharmacodynamic model.

By employing a sequence of epoxide opening, asymmetric alkylation, and fluorination, polyfluorinated cyclopentylamino acids with defined stereochemistries were prepared.

Structure-based drug design led to the identification of a novel class of potent, low MW alkylamine renin inhibitors. Oral administration of lead compound 21l, with MW of 508 and IC50 of 0.47 nM, caused a sustained reduction in mean arterial blood pressure in a double transgenic rat model of hypertension.

Structure-guided drug design led to new alkylamine renin inhibitors with improved in vitro and in vivo potency. Lead compound 21a, has an IC(50) of 0.83nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10mg/kg resulted in >20h reduction of blood pressure in a double transgenic rat model of hypertension.

L'invention concerne de nouveaux composes representes par la formule (I), toute formule parmi les formules I 1 -I 26 Ia 1-3 -lj 1-3 ou leurs sels acceptables sur le plan pharmaceutique, ainsi que leurs compositions pharmaceutiques, utiles pour le traitement de maladies associees a la modulation ou a l'inhibition de 11 β-HSD1 chez des mammiferes. L'invention concerne egalement des compositions pharmaceutiques contenant ces nouveaux composes et leurs procedes d'utilisation afin de diminuer ou de controler la production de Cortisol dans une cellule ou d'inhiber la conversion de cortisone en Cortisol dans une cellule.