The discovery of azepane sulfonamides as potent 11β-HSD1 inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 16, 2009, Pages 4563-4565

  Neelamkavil, Santhosh F ^a   Boyle, Craig D ^a   Chackalamannil, Samuel ^a   Greenlee, William J ^a   Zhang, Lili ^a   Terracina, Giuseppe ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

11 HSD1; 11 HSD2; Azepine sulfonamides; Cortisol; Cortisone; Diabetes; Obesity

Indexed keywords

11BETA HYDROXYSTEROID DEHYDROGENASE 1; 4 OXOPIPERIDINE 1 CARBOXYLIC ACID; 4 PHENYLAZEPANE AMIDE; AZEPINE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; DRUG INHIBITION; DRUG STRUCTURE; DRUG SYNTHESIS; IC 50; STRUCTURE ACTIVITY RELATION;

11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1; ANIMALS; ANTI-INFLAMMATORY AGENTS; AZEPINES; DRUG DISCOVERY; ENZYME INHIBITORS; HUMANS; MICE; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES;

EID: 67651091643     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.07.003     Document Type: Article

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14. Isomers 9 and 10 were separated by silica gel chromatography with 40% hexanes/ethyl acetate as the eluent system.
15. 4 pH 7.5, 30 μM 18β-glycyrrhetinic acid, 1 μg/ml monoclonal anti-cortisol antibody (Biosource) and 2 mg/ml anti-mouse antibody coated scintillation proximity assay (SPA) beads (Amersham Bioscience). The mixture was incubated at room temperature for 2 h with vigorous shaking and analyzed on TopCount scintillation counter.
16. The lower activity in the mouse assay as compared to human makes it challenging to predict human efficacy based on a rodent in vivo model.
17. Representative compounds 27 and 31 showed <10% inhibition in an 11β-HSD2 assay at a concentration of 50 μM implying that these compounds are highly selective inhibitors of 11β-HSD1.
18. Kinetic solubility of selected compounds: (12 = 10 μM, 27 = 200 μM, 23 = 100 μM, 31 = 100 μM). The nephelometric (light scattering) method was used to determine the kinetic solubility of compounds. The test compound (1.0 mg) was dissolved in DMSO at 25 mM. A serial dilution into DMSO was performed and 3 μl of the compound in DMSO at various concentrations was added to the buffer (10 mM phosphate, pH 7.4). Presence of precipitate was detected by nephelometry. Solubility was defined as the highest concentration of material that did not scatter light. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv. Drug Delivery Rev. 2001, 46, 3.