RESUMO
Inhibition of CYP11B1 is a promising therapy for severe diseases caused by excessive cortisol. Enantiomer discrimination provides clues to achieve selectivity that CYP11B1 and homologous CYP11B2 were selectively bound by S- and R-fadrozole, respectively, in distinct binding modes. Pyridyl 4,5,6,7-tetrahydro-4,7-methanobenzo[d]isoxazoles showing a similar binding mode to S-fadrozole in CYP11B1 were designed as potent and selective CYP11B1 inhibitors. Compound 7aa exhibited a highly potent CYP11B1 inhibition similar to that of the drug osilodrostat (IC50's of 9 and 6 nM, respectively) but was 1500-fold more selective over CYP11B2 compared to osilodrostat (selectivity factors of 125 versus 0.08, respectively). Strong reductions of plasma cortisol concentrations by compound 7aa were demonstrated in rats without interference in aldosterone production after oral application. It showed no inhibition against a panel of steroidogenic and hepatic CYP enzymes. Exhibiting a good pharmacokinetic profile, compound 7aa was considered as a drug candidate for further development.
Assuntos
Citocromo P-450 CYP11B2 , Esteroide 11-beta-Hidroxilase , Animais , Fadrozol/farmacologia , Hidrocortisona , Isoxazóis , Oxigenases de Função Mista , RatosRESUMO
Hexahydromethanocarbazole is a privileged scaffold in the discovery of new drugs and photoactive organic materials due to its good balance between structural complexity and minimized entropy penalty upon receptor binding. To address the difficulty of synthesizing this highly desirable bridged polycyclic scaffold, we designed a convenient multicomponent reaction cascade as intercepted Heck addition/C-H activation/C-palladacycle formation/electrophilic attack of ANP/N-palladacycle formation/Buchwald amination. A distinguishing feature of this sophisticated strategy is the successive generation of two key phenylnorbornyl palladium species to control the reaction flow towards desired products. DFT calculations further reveal the crucial roles of Cs2CO3 and 5,6-diester substitutions on the norbornene reactant in preventing multiple side-reactions. This innovative method exhibits a broad scope with good yields, and therefore will enable the construction of natural-product-like compound libraries based on hexahydromethanocarbazole.