Optimization of novel di-substituted cyclohexylbenzamide derivatives as potent 11β-HSD1 inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 5, 2009, Pages 1446-1450

  McMinn, Dustin L ^a   Rew, Yosup ^a   Sudom, Athena ^a   Caille, Seb ^a   DeGraffenreid, Michael ^a   He, Xiao ^a   Hungate, Randall ^a   Jiang, Ben ^a   Jaen, Juan ^a   Julian, Lisa D ^a   Kaizerman, Jacob ^a   Novak, Perry ^a   Sun, Daqing ^a   Tu, Hua ^a   Ursu, Stefania ^a   Walker, Nigel P C ^a   Yan, Xuelei ^a   Ye, Qiuping ^a   Wang, Zhulun ^a   Powers, Jay P ^a  

^a AMGEN INC   (United States)

Author keywords

11 HSD1; Cardiovascular disease; Cyclohexylbenzamides; Diabetes; Hydroxysteroid dehydrogenase; Metabolic syndrome

Indexed keywords

11BETA HYDROXYSTEROID DEHYDROGENASE 1; BENZAMIDE DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL TISSUE; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DOSE RESPONSE; DRUG CYTOTOXICITY; DRUG DESIGN; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME ACTIVITY; ENZYME INHIBITION; EXPERIMENTAL MODEL; IN VITRO STUDY; IN VIVO STUDY; NONHUMAN; ONE POT SYNTHESIS; RAT; SUBSTITUTION REACTION;

11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1; ANIMALS; BENZAMIDES; DOSE-RESPONSE RELATIONSHIP, DRUG; HELA CELLS; HUMANS; MACACA FASCICULARIS; RATS; RATS, SPRAGUE-DAWLEY; STRUCTURE-ACTIVITY RELATIONSHIP;

RATTUS;

EID: 60449117428     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.01.026     Document Type: Article

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33. All compounds were characterized by NMR and LCMS and found to be >95% purity. As described in reference 12c, 11β-HSD1 enzyme activity was determined by measuring the reduction of [3H]-cortisone to [3H]-cortisol. [3H]-cortisol was captured by an anticortisol monoclonal antibody conjugated to scintillation proximity assay (SPA) beads and quantified by scintillation detection. Biochemical enzyme assays were performed with baculovirus-produced recombinant full-length human, rat, or cyno11β-HSD1 as the enzyme source and NADPH as cofactor. Cell-based enzyme assays employed HEK293 cells stably expressing recombinant human full-length 11β-HSD1 as the enzyme source without supplementation of NADPH. IC50 values for enzyme inhibition were calculated with a dose response curve fitting algorithm with at least duplicate sets of samples.
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35. Time point chosen to coincide with Tmax (ca. 2 h) of the compound upon oral administration.
36. PDB database deposition code 3FCO.