LY-404,039

LY-404,039

Clinical data
ATC code	N
Legal status
Legal status	US: Not FDA-approved
Identifiers
IUPAC name (−)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid
PubChem CID	9834591
ChemSpider	8010312 N
Chemical and physical data
Formula	C7H9NO6S
Molar mass	235.214 g/mol
3D model (Jmol)	Interactive image
SMILES C1[C@]([C@@H]2[C@H]([C@@H]2S1(=O)=O)C(=O)O)(C(=O)O)N
InChI InChI=1S/C7H9NO6S/c8-7(6(11)12)1-15(13,14)4-2(3(4)7)5(9)10/h2-4H,1,8H2,(H,9,10)(H,11,12)/t2-,3-,4+,7+/m1/s1 N Key:AVDUGNCTZRCAHH-MDASVERJSA-N N
NY (what is this?)

LY-404,039, also known as pomaglumetad, is an amino acid analog drug that acts as a highly selective agonist for the metabotropic glutamate receptor group II subtypes mGluR₂ and mGluR₃. Pharmacological research has focused on its potential antipsychotic and anxiolytic effects. LY-404,039 is intended as a treatment for schizophrenia and other psychotic and anxiety disorders by modulating glutamatergic activity and reducing presynaptic release of glutamate at synapses in limbic and forebrain areas relevant to these disorders. Human studies investigating therapeutic use of LY-404,039 have focused on the prodrug LY-2140023, a methionine amide of LY-404,039 (also called pomaglumetad methionil or LY-2140023 monohydrate) since LY-404,039 exhibits low oral absorption and bioavailability in humans.

Early human trials using this prodrug form of LY-404,039 gave encouraging results. However, pharmaceutical company Eli Lilly terminated further development of the compound in 2012 after it failed in phase II clinical trials. In September 2013, the results of a randomized, placebo-controlled clinical trial investigating the impact of adjunctive LY-2140023 on prominent negative symptoms in schizophrenia was published and failed to demonstrate any benefit.

In 2015, Denovo Biopharma exclusively licensed LY-2140023 (the prodrug) for further development, having identified "a meaningful subset of patients who showed significantly improved outcomes".

Clinical development of LY-404,039 resulted from efforts to discover potent and selective mGluR agonists for the treatment of psychiatric disorders. LY-404,039 is highly selective for group II metabotropic glutamate receptors mGluR₂ and mGluR₃. These receptors reduce the activity of postsynaptic potentials in the cortex and act by inhibiting the release of glutamate and GABA. LY-404,039 has been shown to act as a potent full agonist at group II mGluRs as demonstrated by its ability to inhibit cyclic adenosine monophosphate, cAMP, formation as a result of stimulation by forskolin. LY-404,039 has been shown to modulate glutamatergic activity in the limbic and forebrain areas, where group II mGlu receptors are most densely localized.