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Biarylpyrazolyl oxadiazole as potent, selective, orally bioavailable cannabinoid-1 receptor antagonists for the treatment of obesity.
J Med Chem. 2008 Nov 27; 51(22):7216-33.JM

Abstract

Since the CB1 cannabinoid receptor antagonist 1 (SR141716, rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity. In the present study, biarylpyrazole analogues based on a pyrazole core coupled with 1,3,4-oxadiazole were synthesized and tested for CB1 receptor binding affinity. Thorough SAR studies to optimize pyrazole substituents as well as 1,3,4-oxadiazole ring led to several novel CB1 antagonists with IC(50) approximately 1 nM for the CB1 receptor binding. Among these analogues, we identified 2-(4-((1H-1,2,4-triazol-1-yl)methyl)-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)-5-(1-(trifluoromethyl)cyclopropyl)-1,3,4-oxadiazole 43c as a promising precandidate for the development as an antiobesity agent.

Authors+Show Affiliations

Central Research Laboratories, Green Cross Corporation, 303 Bojeong-dong, Giheung-gu, Yongin 446-770, Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18954042

Citation

Lee, Suk Ho, et al. "Biarylpyrazolyl Oxadiazole as Potent, Selective, Orally Bioavailable Cannabinoid-1 Receptor Antagonists for the Treatment of Obesity." Journal of Medicinal Chemistry, vol. 51, no. 22, 2008, pp. 7216-33.
Lee SH, Seo HJ, Lee SH, et al. Biarylpyrazolyl oxadiazole as potent, selective, orally bioavailable cannabinoid-1 receptor antagonists for the treatment of obesity. J Med Chem. 2008;51(22):7216-33.
Lee, S. H., Seo, H. J., Lee, S. H., Jung, M. E., Park, J. H., Park, H. J., Yoo, J., Yun, H., Na, J., Kang, S. Y., Song, K. S., Kim, M. A., Chang, C. H., Kim, J., & Lee, J. (2008). Biarylpyrazolyl oxadiazole as potent, selective, orally bioavailable cannabinoid-1 receptor antagonists for the treatment of obesity. Journal of Medicinal Chemistry, 51(22), 7216-33. https://doi.org/10.1021/jm800843r
Lee SH, et al. Biarylpyrazolyl Oxadiazole as Potent, Selective, Orally Bioavailable Cannabinoid-1 Receptor Antagonists for the Treatment of Obesity. J Med Chem. 2008 Nov 27;51(22):7216-33. PubMed PMID: 18954042.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Biarylpyrazolyl oxadiazole as potent, selective, orally bioavailable cannabinoid-1 receptor antagonists for the treatment of obesity. AU - Lee,Suk Ho, AU - Seo,Hee Jeong, AU - Lee,Sung-Han, AU - Jung,Myung Eun, AU - Park,Ji-Hyun, AU - Park,Hyun-Ju, AU - Yoo,Jakyung, AU - Yun,Hoseop, AU - Na,Jooran, AU - Kang,Suk Youn, AU - Song,Kwang-Seop, AU - Kim,Min-ah, AU - Chang,Chong-Hwan, AU - Kim,Jeongmin, AU - Lee,Jinhwa, PY - 2008/10/29/pubmed PY - 2009/4/4/medline PY - 2008/10/29/entrez SP - 7216 EP - 33 JF - Journal of medicinal chemistry JO - J Med Chem VL - 51 IS - 22 N2 - Since the CB1 cannabinoid receptor antagonist 1 (SR141716, rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity. In the present study, biarylpyrazole analogues based on a pyrazole core coupled with 1,3,4-oxadiazole were synthesized and tested for CB1 receptor binding affinity. Thorough SAR studies to optimize pyrazole substituents as well as 1,3,4-oxadiazole ring led to several novel CB1 antagonists with IC(50) approximately 1 nM for the CB1 receptor binding. Among these analogues, we identified 2-(4-((1H-1,2,4-triazol-1-yl)methyl)-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)-5-(1-(trifluoromethyl)cyclopropyl)-1,3,4-oxadiazole 43c as a promising precandidate for the development as an antiobesity agent. SN - 1520-4804 UR - https://www.unboundmedicine.com/medline/citation/18954042/Biarylpyrazolyl_oxadiazole_as_potent_selective_orally_bioavailable_cannabinoid_1_receptor_antagonists_for_the_treatment_of_obesity_ L2 - https://doi.org/10.1021/jm800843r DB - PRIME DP - Unbound Medicine ER -