Pomaglumetad (LY-404,039) is an amino acid analog drug that acts as a highly selective agonist for the metabotropic glutamate receptor group II subtypes mGluR2 and mGluR3.

[5][6] 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.

[7] 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".

[9] pomaglumetad 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.

[1] Pomaglumetad has been shown to modulate glutamatergic activity in the limbic and forebrain areas, where group II mGlu receptors are most densely localized.

[1] The functional activity of pomaglumetad on mGluR receptors has been further demonstrated by investigating the drug's ability to suppress electrically stimulated excitatory postsynaptic potentials, or EPSPs.

Pomaglumetad has been shown to attenuate cortically evoked EPSPs in rat striatal spiny neurons in a concentration-dependent manner, mediated by activation of mGluR2 and mGluR3 receptors.

[16] Despite its apparent efficacy in animal models and in vitro, as well as its highly selective agonistic properties at mGlu2 and mGlu3 receptors, pomaglumetad displayed only 3% oral bioavailability in humans in a phase I clinical trial.

It is suspected that LY-2140023 may balance and normalize dysregulated and hyperactive cortical pyramidal neurons in regions associated with schizophrenia and psychosis such as the thalamus, prefrontal cortex, and limbic system.

In 2007, a randomized phase II clinical trial showed that LY-2140023 taken twice daily for 4 weeks improved schizophrenia symptoms as measured with the PANSS and CGI-S when compared to placebo.

The researchers on the clinical trial hypothesized that the lack of significant difference between LY-2140023 and olanzapine on their outcome measures was due to incorrect dosage of LY-2140023, and that the optimal therapeutic dose was yet to be determined.

[12] However, the results of this study were considered inconclusive because neither the LY-2140023 or the olanzapine (active control) groups demonstrated significant differences in treatment as compared to the placebo.

[21] A phase II, multicenter, randomized, parallel, active-controlled study with an open-label design was conducted in 2013 to investigate tolerability, efficacy and adverse effects of long-term treatment with LY-2140023.

The most common treatment-emergent adverse effects reported with use of the drug include insomnia, nausea, headache, somnolence, affect lability and blood creatine phosphokinase increase.

A long-term study found that there was no statistically significant difference in the time to discontinuation of use due to lack of tolerability between patients using LY-2140023 and other antipsychotic medications.

[22] The company completed a phase II, randomized, double-blind, placebo- and active-controlled, parallel-group-assignment, dose-ranging, inpatient, multi-center clinical trial.

Of the decision to stop development, Jan Lundberg, PhD and president of Lilly Research Laboratories, said "I'm disappointed in what these results mean for patients with schizophrenia who still are searching for options to treat this terrible illness".