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Discovery and optimization of a novel series of N-arylamide oxadiazoles as potent, highly selective and orally bioavailable cannabinoid receptor 2 (CB2) agonists.
J Med Chem. 2008 Aug 28; 51(16):5019-34.JM

Abstract

The CB2 receptor is an attractive therapeutic target for analgesic and anti-inflammatory agents. Herein we describe the discovery of a novel class of oxadiazole derivatives from which potent and selective CB2 agonist leads were developed. Initial hit 7 was identified from a cannabinoid target-biased library generated by virtual screening of sample collections using a pharmacophore model in combination with a series of physicochemical filters. 7 was demonstrated to be a selective CB2 agonist (CB2 EC50 = 93 nM, Emax = 98%, CB1 EC50 > 10 microM). However, this compound exhibited poor solubility and relatively high clearance in rat, resulting in low oral bioavailability. In this paper, we report detailed SAR studies on 7 en route toward improving potency, physicochemical properties, and solubility. This effort resulted in identification of 63 that is a potent and selective agonist at CB2 (EC50 = 2 nM, Emax = 110%) with excellent pharmacokinetic properties.

Authors+Show Affiliations

Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. yuanc@amgen.comNo 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 availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

18680277

Citation

Cheng, Yuan, et al. "Discovery and Optimization of a Novel Series of N-arylamide Oxadiazoles as Potent, Highly Selective and Orally Bioavailable Cannabinoid Receptor 2 (CB2) Agonists." Journal of Medicinal Chemistry, vol. 51, no. 16, 2008, pp. 5019-34.
Cheng Y, Albrecht BK, Brown J, et al. Discovery and optimization of a novel series of N-arylamide oxadiazoles as potent, highly selective and orally bioavailable cannabinoid receptor 2 (CB2) agonists. J Med Chem. 2008;51(16):5019-34.
Cheng, Y., Albrecht, B. K., Brown, J., Buchanan, J. L., Buckner, W. H., DiMauro, E. F., Emkey, R., Fremeau, R. T., Harmange, J. C., Hoffman, B. J., Huang, L., Huang, M., Lee, J. H., Lin, F. F., Martin, M. W., Nguyen, H. Q., Patel, V. F., Tomlinson, S. A., White, R. D., ... Hitchcock, S. A. (2008). Discovery and optimization of a novel series of N-arylamide oxadiazoles as potent, highly selective and orally bioavailable cannabinoid receptor 2 (CB2) agonists. Journal of Medicinal Chemistry, 51(16), 5019-34. https://doi.org/10.1021/jm800463f
Cheng Y, et al. Discovery and Optimization of a Novel Series of N-arylamide Oxadiazoles as Potent, Highly Selective and Orally Bioavailable Cannabinoid Receptor 2 (CB2) Agonists. J Med Chem. 2008 Aug 28;51(16):5019-34. PubMed PMID: 18680277.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discovery and optimization of a novel series of N-arylamide oxadiazoles as potent, highly selective and orally bioavailable cannabinoid receptor 2 (CB2) agonists. AU - Cheng,Yuan, AU - Albrecht,Brian K, AU - Brown,James, AU - Buchanan,John L, AU - Buckner,William H, AU - DiMauro,Erin F, AU - Emkey,Renee, AU - Fremeau,Robert T,Jr AU - Harmange,Jean-Christophe, AU - Hoffman,Beth J, AU - Huang,Liyue, AU - Huang,Ming, AU - Lee,Josie Han, AU - Lin,Fen-Fen, AU - Martin,Matthew W, AU - Nguyen,Hung Q, AU - Patel,Vinod F, AU - Tomlinson,Susan A, AU - White,Ryan D, AU - Xia,Xiaoyang, AU - Hitchcock,Stephen A, Y1 - 2008/08/05/ PY - 2008/8/6/pubmed PY - 2008/9/11/medline PY - 2008/8/6/entrez SP - 5019 EP - 34 JF - Journal of medicinal chemistry JO - J Med Chem VL - 51 IS - 16 N2 - The CB2 receptor is an attractive therapeutic target for analgesic and anti-inflammatory agents. Herein we describe the discovery of a novel class of oxadiazole derivatives from which potent and selective CB2 agonist leads were developed. Initial hit 7 was identified from a cannabinoid target-biased library generated by virtual screening of sample collections using a pharmacophore model in combination with a series of physicochemical filters. 7 was demonstrated to be a selective CB2 agonist (CB2 EC50 = 93 nM, Emax = 98%, CB1 EC50 > 10 microM). However, this compound exhibited poor solubility and relatively high clearance in rat, resulting in low oral bioavailability. In this paper, we report detailed SAR studies on 7 en route toward improving potency, physicochemical properties, and solubility. This effort resulted in identification of 63 that is a potent and selective agonist at CB2 (EC50 = 2 nM, Emax = 110%) with excellent pharmacokinetic properties. SN - 1520-4804 UR - https://www.unboundmedicine.com/medline/citation/18680277/Discovery_and_optimization_of_a_novel_series_of_N_arylamide_oxadiazoles_as_potent_highly_selective_and_orally_bioavailable_cannabinoid_receptor_2__CB2__agonists_ L2 - https://doi.org/10.1021/jm800463f DB - PRIME DP - Unbound Medicine ER -