2. Academic Validation
  3. 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

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

Affiliation

  • 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.
PMID: 26313429 DOI: 10.1021/acs.jmedchem.5b01124
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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