Synthesis and structure-activity relationship of novel diarylpyrazole imide analogues as CB1 cannabinoid receptor ligands

Bioorganic and Medicinal Chemistry

Volumn 17, Issue 8, 2009, Pages 3080-3092

  Song, Kwang Seop ^a   Kim, Min Ju ^a   Seo, Hee Jeong ^a   Lee, Sung Han ^a   Jung, Myung Eun ^a   Kim, Soo Un ^b   Kim, Jeongmin ^a   Lee, Jinhwa ^a  

^a Green Cross Company   (South Korea)

^b Seoul National University   (South Korea)

Author keywords

CB1 receptor; Imide; Methylenediamide; QSAR; Rimonabant; Sulfonamide

Indexed keywords

5 (4 CHLOROPHENYL) 1 (2,4 DICHLOROPHENYL) 4 ETHYLSULFONYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; 5 (4 CHLOROPHENYL) 1 (2,4 DICHLOROPHENYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; 5 (4 CHLOROPHENYL) 1 (2,4 DICHLOROPHENYL) 4 METHYL 1H PYRAZOLE 3 CARBOXYLIC ACID; 5 (4 CHLOROPHENYL) 1 (2,4 DICHLOROPHENYL) 4 METHYL N (2 PROPYLPENTANOYL) 1H PYRAZOLE 3 CARBOXAMIDE; 5 (4 CHLOROPHENYL) 1 (2,4 DICHLOROPHENYL) 4 METHYL N PIVALOYL 1H PYRAZOLE 3 CARBOXAMIDE; 5 (4 CHLOROPHENYL) 1 (2,4 DICHLOROPHENYL) 4 METHYL N TOSYL 1H PYRAZOLE 3 CARBOXAMIDE; 5 (4 CHLOROPHENYL) 1 (2,4 DICHLOROPHENYL) 4 METHYL N(PHENYLSULFONYL) DIMETHYL 1H PYRAZOLE 3 CARBOXAMIDE; 5 (4 CHLOROPHENYL) 1 (2,4 DICHLOROPHENYL) 4 METHYL N,4 DIMETHYL 1H PYRAZOLE 3 CARBOXAMIDE; 5 (4 CHLOROPHENYL) 1 (2,4 DICHLOROPHENYL) N (2 ETHYLBUTANOYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; 5 (4 CHLOROPHENYL) 1 (2,4 DICHLOROPHENYL) N (2 ETHYLHEXANOYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; 5 (4 CHLOROPHENYL) 1 (2,4 DICHLOROPHENYL) N (2,2 DIMETHYLBUTANOYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; 5 (4 CHLOROPHENYL) 1 (2,4 DICHLOROPHENYL) N (3 FLUOROPHENYLSULFONYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; 5 (4 CHLOROPHENYL) 1 (2,4 DICHLOROPHENYL) N (3,3 DIMETHYLBUTANOYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; 5 (4 CHLOROPHENYL) 1 (2,4 DICHLOROPHENYL) N (4 FLUOROPHENYLSULFONYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; 5 (4 CHLOROPHENYL) 1 (2,4 DICHLOROPHENYL) N (ISOPROPYLSULFONYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; 5 (4 CHLOROPHENYL) 1 (2,4 DICHLOROPHENYL) N HEXANOYL 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; 5 (4 CHLOROPHENYL) 1 (2,4 DICHLOROPHENYL) N ISOBUTYRYL 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; 5 (4 CHLOROPHENYL) N (3 CHLOROPHENYLSULFONYL) 1 (2,4 DICHLOROPHENYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; 5 (4 CHLOROPHENYL) N (4 CHLOROPHENYLSULFONYL) 1 (2,4 DICHLOROPHENYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; 5 (4 CHLOROPHENYL) N (CYCLOHEXANECARBONYL) 1 (2,4 DICHLOROPHENYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; 5 (4 CHLOROPHENYL) N (CYCLOPENTANECARBONYL) 1 (2,4 DICHLOROPHENYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; ANTIOBESITY AGENT; CANNABINOID 1 RECEPTOR ANTAGONIST; DIARYLPYRAZOLE IMIDE DERIVATIVE; N (AMINOMETHYL) 5 (4 CHLOROPHENYL) 1 (2,4 DICHLOROPHENYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; N (BENZYLSULFONYL) 5 4 CHLOROPHENYL) 1 (2,4 DICHLOROPHENYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; N (BUTYLSULFONYL) 5 (4 CHLOROPHENYL) 1 (2,4 DICHLOROPHENYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; N BUTYRYL 5 (4 CHLOROPHENYL) 1 (2,4 DICHLOROPHENYL) 4 METHYL 1H PYRAZOLE 3 CARBOXAMIDE; RIMONABANT; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANIMAL EXPERIMENT; ARTICLE; BINDING AFFINITY; CONTROLLED STUDY; DRUG ACTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; HYDROPHOBICITY; MALE; MOUSE; NONHUMAN; QUANTITATIVE STRUCTURE ACTIVITY RELATION; RECEPTOR BINDING; STEREOSPECIFICITY;

ANIMALS; DRUG DESIGN; IMIDES; LIGANDS; MALE; MICE; MICE, INBRED C57BL; PIPERIDINES; PROTEIN BINDING; PYRAZOLES; QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP; RATS; RATS, SPRAGUE-DAWLEY; RECEPTOR, CANNABINOID, CB1;

EID: 64049098487     PISSN: 09680896     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmc.2009.03.006     Document Type: Article

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35. 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.
36. 50 values were not convincingly impressive or attractive enough to make the real compounds.
37. 30b, the 1,3,4-oxadiazole ring, a bioisostere of amide, forms a bidentate H-bond with Lys192, and this explains boosted affinity of the 1,3,4-oxadiazole series of compounds for CB1 receptor. Here we hoped to mimic 1,3,4-oxadiazole ring moiety with an acyclic imide functionality, since they present similarity in several aspects.
38. 19c They did not observe any instability caused by its chemical structure. Neither did us. The synthesis of methylenediamide compounds proved to be uneventful.