Synthesis and SAR of 2-aryl-3-aminomethylquinolines as agonists of the bile acid receptor TGR5

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 19, 2010, Pages 5718-5721

  Herbert, Mark R ^a   Siegel, Dana L ^a   Staszewski, Lena ^a   Cayanan, Charmagne ^a   Banerjee, Urmi ^a   Dhamija, Sangeeta ^a   Anderson, Jennifer ^a   Fan, Amy ^a   Wang, Li ^a   Rix, Peter ^a   Shiau, Andrew K ^a   Rao, Tadimeti S ^a   Noble, Stewart A ^a   Heyman, Richard A ^a   Bischoff, Eric ^a   Guha, Mausumee ^a   Kabakibi, Ayman ^a   Pinkerton, Anthony B ^a,b  

^a Kalypsys Inc   (United States)

^b BURNHAM INSTITUTE   (United States)

Author keywords

Bile acids; Diabetes; GPCRs; TGR5

Indexed keywords

BILE ACID; QUINOLINE DERIVATIVE; RECEPTOR;

ANIMAL EXPERIMENT; ANIMAL MODEL; AREA UNDER THE CURVE; ARTICLE; DIABETES MELLITUS; DRUG CLEARANCE; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HUMAN CELL; MOUSE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; ORAL GLUCOSE TOLERANCE TEST; SCREENING; STRUCTURE ACTIVITY RELATION;

ANIMALS; DIABETES MELLITUS, TYPE 2; GLUCAGON-LIKE PEPTIDE 1; HYDROXYQUINOLINES; MICE; QUINOLINES; RECEPTORS, G-PROTEIN-COUPLED; STRUCTURE-ACTIVITY RELATIONSHIP; THIOPHENES;

RODENTIA;

EID: 77957581107     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.08.014     Document Type: Article

References (23)

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17. 6/mL and incubated overnight at 37 °C in an atmosphere of 10% CO2 and 95% humidity. The next day, test agents were added to cells in the presence of 1 mM IBMX and incubated for 30 minutes at 37 °C. Intracellular cAMP was then measured by TR-FRET using a commercially available LANCE kit (Perkin-Elmer, Boston MA). All compounds were tested in 20-point dose response, n = 3. Compounds were full agonists on both the hTGR5 and mTGR5 receptors, comparable to cholic acid.
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19. Complete experimental procedures and spectral data can be found in: Pinkerton, A. B.; Kabakibi, A.; Herbert, M. R.; Siegel, D. L. WO2008/097976.
20. Preliminary data presented at: Guha, M.; Pinkerton, A.; Banerjee, U.; Dhamija, S.; Anderson, J.; Herbert, M.; Siegel, D.; Hoffman, T.; Staszewski, L.; Cayanan, C.; Shiau, A.; Rao, T.; Noble, S.; Kabakibi, A. National Meeting of the American Diabetes Association, San Francisco, CA, June, 2008.
21. Compound 32 as a bis-HCl salt (30 mpk) in CMC (0.5%)/Tween 20 (0.25%) was dosed orally to DIO mice (n = 6 mice per time point, fasted for 18 h) 15 min prior to an oral dextrose bolus (2 g/kg in saline). Blood was collected from the tail vein at 3, 6, 9, 12, 15, and 20 min post dose. To prevent the degradation of GLP-1, a sub-optimal dose of vildagliptin (0.1 mpk) was given 25 min prior to dextrose dosing. Plasma GLP-1 was measured by ELISA. Data is represented as plasma GLP-1 level at 9 min post dextrose dose.
22. Compound 32 bis-HCl salt (30 mpk) in CMC (0.5%)/Tween 20 (0.25%) was dosed orally to DIO mice (n = 6 mice per time point, fasted for 18 h) 15 min prior to an OGTT (2 g/kg dextrose in saline). Blood was collected from the tail vein at 0, 15, 20, 30, 60, and 120 min post OGTT, and plasma glucose level was measured using a hand-held glucose meter. Data is represented as glucose AUC post OGTT.
23. Compounds 32 and 35 were screened in a CEREP panel of approximately 30 targets that could potentially affect glucose or GLP-1 levels and their activity was found to be <50% of optimal at 10 μM confirming a TGR5 mechanism of action.