Synthesis and pharmacological characterization of C4-disubstituted analogs of 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate: identification of a potent, selective metabotropic glutamate receptor agonist and determination of agonist-bound human mGlu2 and mGlu3 amino terminal domain structures

  • J Med Chem. 2015 Feb 26;58(4):1776-94. doi: 10.1021/jm501612y.
James A Monn  1 ,  Lourdes Prieto ,  Lorena Taboada ,  Concepcion Pedregal ,  Junliang Hao ,  Matt R Reinhard ,  Steven S Henry ,  Paul J Goldsmith ,  Christopher D Beadle ,  Lesley Walton ,  Teresa Man ,  Helene Rudyk ,  Barry Clark ,  David Tupper ,  S Richard Baker ,  Carlos Lamas ,  Carlos Montero ,  Alicia Marcos ,  Jaime Blanco ,  Mark Bures ,  David K Clawson ,  Shane Atwell ,  Frances Lu ,  Jing Wang ,  Marijane Russell ,  Beverly A Heinz ,  Xushan Wang ,  Joan H Carter ,  Chuanxi Xiang ,  John T Catlow ,  Steven Swanson ,  Helen Sanger ,  Lisa M Broad ,  Michael P Johnson ,  Kelly L Knopp ,  Rosa M A Simmons ,  Bryan G Johnson ,  David B Shaw ,  David L McKinzie
Affiliations
  • 1. Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition, and ⊥Neuroscience Research, Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
PMID: 25602126 DOI: 10.1021/jm501612y
Abstract

As part of our ongoing research to identify novel agents acting at metabotropic glutamate 2 (mGlu2) and 3 (mGlu3) receptors, we have previously reported the identification of the C4α-methyl analog of mGlu2/3 receptor agonist 1 (LY354740). This molecule, 1S,2S,4R,5R,6S-2-amino-4-methylbicyclo[3.1.0]hexane-2,6-dicarboxylate 2 (LY541850), exhibited an unexpected mGlu2 agonist/mGlu3 antagonist pharmacological profile, whereas the C4β-methyl diastereomer (3) possessed dual mGlu2/3 receptor agonist activity. We have now further explored this structure-activity relationship through the preparation of cyclic and acyclic C4-disubstituted analogs of 1, leading to the identification of C4-spirocyclopropane 5 (LY2934747), a novel, potent, and systemically bioavailable mGlu2/3 receptor agonist which exhibits both antipsychotic and analgesic properties in vivo. In addition, through the combined use of protein-ligand X-ray crystallography employing Recombinant human mGlu2/3 receptor amino terminal domains, molecular modeling, and site-directed mutagenesis, a molecular basis for the observed pharmacological profile of compound 2 is proposed.

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