Design, synthesis, and analysis of antagonists of GPR55: Piperidine-substituted 1,3,4-oxadiazol-2-ones

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

Meza-Avina, Maria Elena¹  Lingerfelt, Mary A.¹  Console-Bram, Linda M.²  Gamage, Thomas F.²  Sharir, Haleli²  Gettys, Kristen E.¹  Hurst, Dow P.¹  Kotsikorou, Evangelia³  Shore, Derek M.¹  Caron, Marc G.⁴  Rao, Narasinga¹  Barak, Larry S.⁴  Abood, Mary E.²  Reggio, Patricia H.¹  Croatt, Mitchell P.¹ 

[1] Univ N Carolina, Nat Prod & Drug Discovery Ctr, Dept Chem & Biochem, Greensboro, NC 27402 USA

[2] Temple Univ, Ctr Substance Abuse Res, Philadelphia, PA 19140 USA

[3] Univ Texas Pan Amer, Dept Chem, Edinburg, TX 78539 USA

[4] Duke Univ, Med Ctr, Durham, NC 27709 USA

关键词: GPR55;    Neuropathic pain;    GPCR;    Antagonist;    Cancer;   

DOI  :  10.1016/j.bmcl.2016.02.030

来源: Elsevier

【 摘 要 】

A series of 1,3,4-oxadiazol-2-ones was synthesized and tested for activity as antagonists at GPR55 in cellular beta-arrestin redistribution assays. The synthesis was designed to be modular in nature so that a sufficient number of analogues could be rapidly accessed to explore initial structure-activity relationships. The design of analogues was guided by the docking of potential compounds into a model of the inactive form of GPR55. The results of the assays were used to learn more about the binding pocket of GPR55. With this oxadiazolone scaffold, it was determined that modification of the aryl group adjacent to the oxadiazolone ring was often detrimental and that the distal cyclopropane was beneficial for activity. These results will guide further exploration of this receptor. (C) 2016 Elsevier Ltd. All rights reserved.

【 授权许可】

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