Synthesis and Pharmacological Characterization of C4-(Thiotriazolyl)-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1R,2S,4R,5R,6R)-2-Amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2812223), a Highly Potent, Functionally Selective mGlu2 Receptor Agonist

  • J Med Chem. 2015 Sep 24;58(18):7526-48. doi: 10.1021/acs.jmedchem.5b01124.
James A Monn  1 ,  Lourdes Prieto  1 ,  Lorena Taboada  1 ,  Junliang Hao  1 ,  Matthew R Reinhard  1 ,  Steven S Henry  1 ,  Christopher D Beadle  1 ,  Lesley Walton  1 ,  Teresa Man  1 ,  Helene Rudyk  1 ,  Barry Clark  1 ,  David Tupper  1 ,  S Richard Baker  1 ,  Carlos Lamas  1 ,  Carlos Montero  1 ,  Alicia Marcos  1 ,  Jaime Blanco  1 ,  Mark Bures  1 ,  David K Clawson  1 ,  Shane Atwell  1 ,  Frances Lu  1 ,  Jing Wang  1 ,  Marijane Russell  1 ,  Beverly A Heinz  1 ,  Xushan Wang  1 ,  Joan H Carter  1 ,  Brian G Getman  1 ,  John T Catlow  1 ,  Steven Swanson  1 ,  Bryan G Johnson  1 ,  David B Shaw  1 ,  David L McKinzie  1
Affiliations
  • 1. Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
Abstract

Identification of orthosteric mGlu(2/3) receptor agonists capable of discriminating between individual mGlu2 and mGlu3 subtypes has been highly challenging owing to the glutamate-site sequence homology between these proteins. Herein we detail the preparation and characterization of a series of molecules related to (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate 1 (LY354740) bearing C4-thiotriazole substituents. On the basis of second messenger responses in cells expressing other Recombinant human mGlu2/3 subtypes, a number of high potency and efficacy mGlu2 receptor agonists exhibiting low potency mGlu3 partial agonist/antagonist activity were identified. From this, (1R,2S,4R,5R,6R)-2-amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 14a (LY2812223) was further characterized. Cocrystallization of 14a with the amino terminal domains of hmGlu2 and hmGlu3 combined with site-directed mutation studies has clarified the underlying molecular basis of this unique pharmacology. Evaluation of 14a in a rat model responsive to mGlu2 receptor activation coupled with a measure of central drug disposition provides evidence that this molecule engages and activates central mGlu2 receptors in vivo.

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