Chappell Mark D, Li Renhua, Smith Stephon C, Dressman Bruce A, Tromiczak Eric G, Tripp Allie E, Blanco Maria-Jesus, Vetman Tatiana, Quimby Steven J, Matt James, Britton Thomas C, Fivush Adam M, Schkeryantz Jeffrey M, Mayhugh Daniel, Erickson Jon A, Bures Mark G, Jaramillo Carlos, Carpintero Mercedes, Diego José Eugenio de, Barberis Mario, Garcia-Cerrada Susana, Soriano José F, Antonysamy Stephen, Atwell Shane, MacEwan Iain, Condon Bradley, Sougias Christine, Wang Jing, Zhang Aiping, Conners Kris, Groshong Chris, Wasserman Stephen R, Koss John W, Witkin Jeffrey M, Li Xia, Overshiner Carl, Wafford Keith A, Seidel Wesley, Wang Xu-Shan, Heinz Beverly A, Swanson Steven, Catlow John T, Bedwell David W, Monn James A, Mitch Charles H, Ornstein Paul L
Discovery Chemistry Synthesis Group, Centro de Investigación Lilly S.A. Avda. de la Industria , 30 Alcobendas, Madrid 28108, Spain.
Structural Biology, Lilly Biotechnology Center, Eli Lilly and Company , San Diego, California 92121, United States.
J Med Chem. 2016 Dec 22;59(24):10974-10993. doi: 10.1021/acs.jmedchem.6b01119. Epub 2016 Dec 6.
As part of our ongoing efforts to identify novel ligands for the metabotropic glutamate 2 and 3 (mGlu) receptors, we have incorporated substitution at the C3 and C4 positions of the (1S,2R,5R,6R)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid scaffold to generate mGlu antagonists. Exploration of this structure-activity relationship (SAR) led to the identification of (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride (LY3020371·HCl, 19f), a potent, selective, and maximally efficacious mGlu antagonist. Further characterization of compound 19f binding to the human metabotropic 2 glutamate (hmGlu) site was established by cocrystallization of this molecule with the amino terminal domain (ATD) of the hmGlu receptor protein. The resulting cocrystal structure revealed the specific ligand-protein interactions, which likely explain the high affinity of 19f for this site and support its functional mGlu antagonist pharmacology. Further characterization of 19f in vivo demonstrated an antidepressant-like signature in the mouse forced-swim test (mFST) assay when brain levels of this compound exceeded the cellular mGlu IC value.
作为我们持续寻找代谢型谷氨酸2和3（mGlu）受体新型配体工作的一部分，我们在(1S,2R,5R,6R)-2-氨基-双环[3.1.0]己烷-2,6-二羧酸骨架的C3和C4位置引入取代基以生成mGlu拮抗剂。对这种构效关系（SAR）的探索导致了(1S,2R,3S,4S,5R,6R)-2-氨基-3-[(3,4-二氟苯基)硫烷基甲基]-4-羟基-双环[3.1.0]己烷-2,6-二羧酸盐酸盐（LY3020371·HCl，19f）的鉴定，它是一种强效、选择性且最大效能的mGlu拮抗剂。通过该分子与代谢型谷氨酸2（hmGlu）受体蛋白的氨基末端结构域（ATD）共结晶，进一步确定了化合物19f与hmGlu位点结合的特征。所得的共晶体结构揭示了特定的配体-蛋白相互作用，这可能解释了19f对该位点的高亲和力，并支持其作为功能性mGlu拮抗剂的药理学特性。当该化合物在脑内的水平超过细胞mGlu IC值时，对19f在体内的进一步表征表明其在小鼠强迫游泳试验（mFST）中具有抗抑郁样特征。
