Oxadiazole-diarylpyrazole 4-carboxamides as cannabinoid CB1 receptor ligands

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 7, 2009, Pages 1899-1902

  Lee, Suk Ho ^a   Seo, Hee Jeong ^a   Kim, Min Ju ^a   Kang, Suk Youn ^a   Song, Kwang Seop ^a   Lee, Sung Han ^a   Jung, Myung Eun ^a   Kim, Jeongmin ^a   Lee, Jinhwa ^a  

^a Green Cross Company   (South Korea)

Author keywords

Antiobesity; Cannabinoid receptor antagonist; Carboxamide; Oxadiazole; Rimonabant

Indexed keywords

5 (4 BROMOPHENYL) 3 (5 TERT BUTYL 1,3,4 OXADIAZOL 2 YL) 1 (2,4 DICHLOROPHENYL) N (PYRIDIN 2 YL) 1H PYRAZOLE 4 CARBOXAMIDE; 5 (4 BROMOPHENYL) 3 (5 TERT BUTYL 1,3,4 OXADIAZOL 2 YL) 1 (2,4 DICHLOROPHENYL) N PHENYL 1H PYRAZOLE 4 CARBOXAMIDE; AMIDE; CANNABINOID 1 RECEPTOR; CANNABINOID 1 RECEPTOR ANTAGONIST; OXADIAZOLE DERIVATIVE; PYRAZOLE DERIVATIVE; RIMONABANT; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL TISSUE; ARTICLE; BINDING AFFINITY; CONTROLLED STUDY; CYCLIZATION; DRUG RECEPTOR BINDING; DRUG SELECTIVITY; DRUG SYNTHESIS; IC 50; IN VITRO STUDY; NONHUMAN; OBESITY; RAT;

ANIMALS; ANTI-OBESITY AGENTS; CHO CELLS; CRICETINAE; CRICETULUS; INHIBITORY CONCENTRATION 50; LIGANDS; OBESITY; OXADIAZOLES; PYRAZOLES; RECEPTOR, CANNABINOID, CB1; STRUCTURE-ACTIVITY RELATIONSHIP; TRANSFECTION;

EID: 61849137327     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.02.063     Document Type: Article

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31. 21 Competitive binding assays were performed as described. Briefly, approximately 10 μg of rat cerebella membranes (containing CB1 receptor) or cell membranes (containing CB2 receptor) were incubated in 96-well plate with TME buffer containing 0.5% essentially fatty acid free bovine serum albumin (BSA), 3 nM [3H]WIN55,212-2 (for CB2 receptor, NEN; specific activity 50-80 Ci/mmol) or 3 nM ([3H]CP55,940, [3H]2-[(1S,2R,5S)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol, for CB1 receptor, NEN; specific activity 120-190 Ci/mmol) and various concentrations of the synthesized cannabinoid ligands in a final volume of 200 μL. The assays were incubated for 1 h at 30 °C and then immediately filtered over GF/B glass fiber fiber filter (PerkinElmer Life and Analytical Sciences, Boston, MA) that had been soaked in 0.1% PEI for 1 h by a cell harvester (PerkinElmer Life and Analytical Sciences, Boston, MA). Filters were washed five times with ice-cold TBE buffer containing 0.1% essentially fatty acid free BSA, followed by oven-dried for 60 min and then placed in 5 mL of scintillation fluid (Ultima Gold XR; PerkinElmer Life and Analytical Sciences, Boston, MA), and radioactivity was quantitated by liquid scintillation spectrometry. In CB1 and CB2 receptor competitive binding assay, nonspecific binding was assessed using 1 μM rimonabant and 1 μM WIN55,212-2, respectively. Specific binding was defined as the difference between the binding that occurred in the presence and absence of 1 μM concentrations of rimonabant or WIN55,212-2 and was 70-80% of the total binding. IC50 was determined by nonlinear regression analysis using Graph-Pad PRISM. All data were collected in triplicate and IC50 was determined from three independent experiments.
32. As of November 5, 2008, Sanofi-Aventis, Merck, and Pfizer announced that they have decided to discontinue their ongoing clinical development programs about rimonabant (SR141716), taranabant (MK-0364), and otenabant (CP-945,598), respectively based on changing regulatory perspectives on the risk/benefit profile of the CB1 class and likely new regulatory requirements for approval.
33. {A table is presented}
34. {A table is presented}
35. As pointed out by a reviewer, compound 12s represents the best diarylpyrazole-oxadiazole to date, and the selectivity is impressive. A bulky group such as (4-chlorophenyl)cyclopropyl in compound 12 appears to deactivate CB2 receptor binding affinity while maintaining its activity for CB1 receptor, thereby improving CB2/CB1 selectivity.