RGD Reference Report - Discovery of 2-[5-(4-chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-ethyl-1H-pyrazol-3-yl]-1, 5,5-trimethyl-1,5-dihydro-imidazol-4-thione (BPR-890) via an active metabolite. A novel, potent and selective cannabinoid-1 receptor inverse agonist with high antiobesity efficacy in DIO mice. - Rat Genome Database

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Discovery of 2-[5-(4-chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-ethyl-1H-pyrazol-3-yl]-1, 5,5-trimethyl-1,5-dihydro-imidazol-4-thione (BPR-890) via an active metabolite. A novel, potent and selective cannabinoid-1 receptor inverse agonist with high antiobesity efficacy in DIO mice.

Authors: Wu, CH  Hung, MS  Song, JS  Yeh, TK  Chou, MC  Chu, CM  Jan, JJ  Hsieh, MT  Tseng, SL  Chang, CP  Hsieh, WP  Lin, Y  Yeh, YN  Chung, WL  Kuo, CW  Lin, CY  Shy, HS  Chao, YS  Shia, KS 
Citation: Wu CH, etal., J Med Chem. 2009 Jul 23;52(14):4496-510.
RGD ID: 2314629
Pubmed: PMID:19530697   (View Abstract at PubMed)
DOI: DOI:10.1021/jm900471u   (Journal Full-text)

By using the active metabolite 5 as an initial template, further structural modifications led to the identification of the titled compound 24 (BPR-890) as a highly potent CB1 inverse agonist possessing an excellent CB2/1 selectivity and remarkable in vivo efficacy in diet-induced obese mice with a minimum effective dose as low as 0.03 mg/kg (po qd) at the end of the 30-day chronic study. Current SAR studies along with those of many existing rimonabant-mimicking molecules imply that around the pyrazole C3-position, a rigid and deep binding pocket should exist for CB1 receptor. In addition, relative to the conventional carboxamide carbonyl, serving as a key hydrogen-bond acceptor during ligand-CB1 receptor interaction, the corresponding polarizable thione carbonyl might play a more critical role in stabilizing the Asp366-Lys192 salt bridge in the proposed CB1-receptor homology model and inducing significant selectivity for CB1R over CB2R.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
obesity  ISOCnr1 (Mus musculus)2314629; 2314629 RGD 
obesity  IMP 2314629 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cnr1  (cannabinoid receptor 1)

Genes (Mus musculus)
Cnr1  (cannabinoid receptor 1)

Genes (Homo sapiens)
CNR1  (cannabinoid receptor 1)


Additional Information