Synthesis and optimization of picolinamide derivatives as a novel class of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors

Discovery of 2-((R)-4-(2-Fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)-N-((1R,2s,3S,5S,7S)-5-hydroxyadamantan-2-yl)pyrimidine-4-carboxamide (SKI2852): A Highly Potent, Selective, and Orally Bioavailable Inhibitor of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1)

“…The hydroxy-adamantyl group and (R)-2-methyl-4-phenylpiperazin-1-yl moiety were maintained in the novel pyrimidine-4-carboxamide derivatives, and diverse functional groups were introduced at the 4-position of the phenyl ring (17a−f). Similar to the results of our previous SAR study on picolinamide analogues, 29 the compounds that were substituted with hydrophilic groups (17d−f) were approximately 2 times more potent in the cellular assay than the derivatives with hydrophobic substituents (17a−c). Among them, compound 17e showed the highest cellular potency, good metabolic stability, and acceptable activity in the ex vivo PD assay (48% and 81% inhibition at 10 mg/kg in the liver and EPF, respectively).…”

“…The replacement of the cyano group at the 4-position of the phenyl ring with a methylsulfonyl group resulted in an increase in its biochemical and cellular potencies, and modifying the piperazine ring by introducing an (R)-methyl group substantially improved the PK properties. This lead compound 9 demonstrated excellent activity in a mouse ex vivo pharmacodynamic (PD) model and reduced the blood glucose, LDL cholesterol, and triglyceride levels in ob/ob mice after oral administration 29 (Figure 2). However, profiling in drug metabolism studies showed that compound 9 was a moderate-to-strong inhibitor of CYP3A4 and CYP2C19, exhibiting IC 50 values of 0.97 and 3.7 μM, respectively.…”

“…We have previously described a novel class of 11β-HSD1 inhibitors that contain the picolinamide core. , Structural modifications of the initial hit compound 7 resulted in the discovery of the highly potent and metabolically stable compound 8 . High potency was achieved by the incorporation of a hydroxy-adamantyl group, and the replacement of the piperidine ring with 1-(4-cyanophenyl)­piperazine led to a significant improvement in metabolic stability .…”

Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions

“…Park and co-workers (SK Chemicals) were able to selectively functionalize unprotected piperazine 90 at the less-hindered nitrogen of the nucleophile ( Scheme 14 b). 95 In the synthesis of a potential agent for treating type II diabetes, agent 92 , a C–N bond was first established between aryl bromide 89 and 90 to provide intermediate 91 . Then, a second N-arylation took place at the 2-substituted piperazine amine to afford the title compound.…”

Multi-Targeted Molecular Docking, Pharmacokinetics, and Drug-Likeness Evaluation of Okra-Derived Ligand Abscisic Acid Targeting Signaling Proteins Involved in the Development of Diabetes

“…Cortisol promotes pre-adipocyte differentiation into mature adipocytes, resulting in adipose tissue hyperplasia. By modulating cortisone/cortisol levels, selective inhibition of this enzyme can be a novel treatment for T2DM and hyperlipidemia [ 16 , 17 , 18 , 19 ]. Obesity, diabetes, wound healing, and muscular atrophy are glucocorticoid-related disorders, and inhibiting 11β-HSD1 has many therapeutic values, including T2DM and hyperlipidemia.…”