Substituted pyrimidines as cannabinoid CB1 receptor ligands

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 16, 2009, Pages 4692-4697

  Kim, Min Ju ^a   Kim, Jong Yup ^a   Seo, Hee Jeong ^a   Lee, Junwon ^a   Lee, Sung Han ^a   Kim, Mi Soon ^a   Kang, Jahyo ^b   Kim, Jeongmin ^a   Lee, Jinhwa ^a  

^a Green Cross Company   (South Korea)

^b Sogang University   (South Korea)

Author keywords

Antagonist; Antiobesity; Pyrimidine; Rimonabant; Taranabant

Indexed keywords

3 BROMOPHENYLACETIC ACID; 4 BENZYLOXAZOLIDIN 2 ONE; ANTIOBESITY AGENT; BENZYL DERIVATIVE; CANNABINOID 1 RECEPTOR; CANNABINOID 1 RECEPTOR ANTAGONIST; CYCLOHEXYLAMINE; N4 [3 (3 BROMOPHENYL) 4 (4 CHLOROPHENYL)BUTAN 2 YL] N6 BUTYLPYRIMIDINE 4,6 DIAMINE; PHENYLACETIC ACID DERIVATIVE; PYRIMIDINE DERIVATIVE; RIMONABANT; TARANABANT; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; BINDING AFFINITY; DRUG DESIGN; DRUG RECEPTOR BINDING; DRUG SCREENING; DRUG SELECTIVITY; DRUG SYNTHESIS; IC 50; NONHUMAN; OBESITY; RAT; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTI-OBESITY AGENTS; LIGANDS; PYRIMIDINES; RATS; RATS, SPRAGUE-DAWLEY; RECEPTOR, CANNABINOID, CB1;

EID: 67651120077     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.06.069     Document Type: Article

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30. 16 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 in our experiments.
31. 3) δ 8.30 (s, 1H), 7.36 (d, J = 8.00 Hz, 1H), 7.25 (s, 2H), 7.18-7.12 (m, 3H), 6.99-6.94 (m, 3H), 6.18 (br, 1H), 3.11-3.07 (m, 1H), 3.02-2.99 (m, 1H), 2.94-2.88 (m, 2H), 1.08 (d, J = 6.4 Hz, 3H). MH+ 450.
32. 3) δ 7.99 (s, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.25 (s, 3H), 7.12-7.03 (m, 3H), 7.00-6.96 (m, 2H), 4.94 (br, 1H), 3.9 (br, 1H), 3.26-2.89 (m, 5H), 1.66-1.59 (m, 2H), 1.51-1.39 (m, 2H), 1.10 (d, J = 6.8 Hz, 2H), 0.97 (t, J = 7.2 Hz, 3H). MH+ 487.
33. 50 = 5.0 ± 1.0 nM) in each different assay (>1500 compounds tested). Therefore, we believe that all SAR discussions in the manuscript are scientifically meaningful.
34. As pointed out by a referee, substituted pyrimidines described in this report do not look like derivatives of acyclic amide taranabant. Rather they might look more like analogues of rimonabant, having pyrimidine heterocycle at the center replacing pyrazole.
35. This Letter describes conformationally constrained analogues of taranabant. Such conformationally constraining approaches have already been described for the CB1 receptor antagonist rimonabant.