LY-404,039

LY-404,039
Systematic (IUPAC) name
(−)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid
Clinical data
Legal status
  • Not FDA-Approved
Identifiers
ATC code N
PubChem CID 9834591
ChemSpider 8010312 N
Chemical data
Formula C7H9NO6S
Molar mass 235.214 g/mol
 NYesY (what is this?)  (verify)

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.[1] 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.[2] 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.[2]

Early human trials using this prodrug form of LY-404,039 gave encouraging results.[2][3][4] However, pharmaceutical company Eli Lilly terminated further development of the compound in 2012 after it failed in phase II clinical trials.[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]

Pharmacology

Mechanism of action and pharmacodynamics

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.[1] These receptors reduce the activity of postsynaptic potentials in the cortex and act by inhibiting the release of glutamate and GABA.[8] 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.[1] 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.

The specific binding of LY-404,039 to human cloned mGlu receptors has been found to be highest for mGluR2 (Ki = 149 +/- 11 nM) and relatively high for mGluR3 (Ki = 92 +/-14 nM).[1] Research suggests that it does not have any appreciable affinity for other metabotropic glutamate receptors, ionotropic NMDA receptors, or kainate receptors, nor does it appear to have any affinity for adrenergic, benzodiazepine/GABAergic, histaminergic or muscarinic receptors.[1] The functional activity of LY-404,039 on mGluR receptors has been further demonstrated by investigating the drug's ability to suppress electrically stimulated excitatory postsynaptic potentials, or EPSPs. LY-404,039 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.[1] This suppressive effect of LY-404,039 on stimulated EPSPs is reversed by the use of mGluR2/3 antagonists, such as LY341495.

LY-404,039 possesses partial agonist actions at D2 receptors and inhibits the binding of the D2-specific antagonist [3H]domperidone to human cloned D2 receptors.[9] It increases the release of dopamine as well as its metabolites DOPAC and HVA in the prefrontal cortex in a manner similar to the atypical antipsychotic clozapine.[1] LY-404,039 also appears to have some effects on serotonin. It has been shown that LY-404,039 increases serotonin turnover, increasing the ratio of 5-HIAA to 5-HT, and suppresses serotonin-induced glutamate release in the prefrontal cortex.[1]

There is disagreement in the literature as to the possible agonistic action that LY-404,039 has on dopamine receptors.[10] Attempts by Eli Lilly and AstraZeneca to replicate findings showing potent partial agonist action of mGluR2/3 agonists at D2 receptors were unsuccessful.

Novelty

Based on the glutamate hypothesis of schizophrenia, glutamate receptor agonists have been suggested as an effective treatment for psychotic patients.[11] LY-404,039 was one of the first drugs to be suggested as effective in treating psychosis without any apparent interference in dopaminergic function.[12] Existing antipsychotic medications primarily treat schizophrenia by acting as antagonists at D2 receptors, while LY-404,039 has very low affinity for biogenic amine receptors.[11]

Structurally, LY-404,039 is a close relative to other mGluR2/3 orthosteric agonists eglumetad, LY-379,268, LY-389,795, and MGS-008, all of which are members of the bicyclohexane family.[10] LY-404,039 was the preferred drug candidate for further development due to its antipsychotic efficacy and lack of motor coordination effects at doses up to 30 mg/kg.[13]

Animal studies

The pharmacokinetic profile of LY-404,039 has been primarily investigated in rodent models. It has shown high in vitro potency and efficacy as well as antipsychotic potential in animal studies.[1][13] In overnight-fasted rats, intravenous dosing resulted in an AUC0-24 value of 2.9 ug*h/ml and a Cmax value of 7.5 ug/ml.[13] Oral administration resulted in an AUC0-24 value of 7.2 ug*h/ml and a Cmax value of 4.0 ug/ml. The oral bioavailability in these rats was found to be 63%.

LY-404,039 demonstrates similar efficacy to clozapine for the treatment of psychotic symptoms in amphetamine and PCP animal models.[1][13] In both mice and rat studies, the drug demonstrates inhibition of induced hyperlocomotion and conditioned avoidance responding. LY-404,039 has also been shown to attenuate fear-potentiated startle and reduce marble burying in rodents, predictive of anxiolytic efficacy.[14] Use of LY-404,039 in rodent models indicates a lack of motor side effects or impairment, as determined by experiments using a rotarod. There also appear to be no sedative effects.

Animal studies and neurochemical models have also shown that use of LY-404,039 augments the efficacy of known antipsychotics, predictive of potential clinical efficacy in schizophrenia treatment.[15] Assays of locomotion and conditioned avoidance showed evidence of synergy between LY-404,039 and antipsychotic medication, as well as an absence of motor impairment typically observed with high doses of antipsychotic medications. The combination of LY-404,039 (5 and 20 mg/kg) and risperidone (0.3 mg/kg) achieved prefrontal cortical dopamine efflux significantly higher than that observed with treatment by either drug alone.[15]

Clinical use of LY-2140023

Despite its apparent efficacy in animal models and in vitro, as well as its highly selective agonistic properties at mGlu2 and mGlu3 receptors, LY-404,039 displayed only 3% oral bioavailability in humans in a phase I clinical trial.[2][10] A single dose of 200 mg results in an AUC value of 900 ng*h/ml.[16] The drug’s poor uptake has been cited as, in part, due to its interaction with the peptide transporter PepT 1. This led to the synthesis and development of LY-2140023, an oral methionine prodrug of LY-404,039 (also known as pomaglumetad methionil), in 2010 for oral treatment of schizophrenia by Eli Lilly.[10]

Pomaglumetad methionil

Synthesis and pharmacology

LY-2140023 was identified using the analogous peptide prodrug approach used previously for talaglumetad, the prodrug of eglumetad.[10] Synthesis was the result of preparation of LY-389795 followed by oxidation to LY-404,039 and coupling with L-methionine.[13] LY-2140023 uses a human peptide transporter and hydrolytic pathways to deliver LY-404,039 to systemic circulation in humans.[11][17] It is rapidly absorbed and hydrolyzed to produce active LY-404,039 (~70% conversion), increasing its estimated bioavailability to 49%.[11][13] In humans, use of LY-2140023 resulted in significantly higher plasma levels of LY-404,039 compared with oral administration of LY-404039.[18] LY-2140023 appears to be an inactive prodrug, as Ki values for the drug have been found to be greater than 100 µM.[1]

Treatment for schizophrenia

LY-2140023 is the first drug acting on mGlu receptors that has been studied in humans for the treatment of schizophrenia.[2] It has been proposed as useful treatment of both positive and negative symptoms by acting as a selective agonist at mGlu receptors and modulating glutamatergic neurotransmission. 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.[11] Clinical trials using LY-2140023 have investigated its use as a therapy when administered alone and as an adjuvant therapy used in addition to atypical antipsychotics.

Dosage and usage

The dosage of LY-2140023 given to patients has varied by clinical trial, though dosages have typically ranged between 10 mg and 40 mg twice daily (BID). In an early phase II monotherapy trial, the dosage shown to be efficacious was 40 mg BID.[2] Later trials investigating the use of LY-2140023 as an adjuvant to the antipsychotic medications already used by patients participating in the study utilized a lower dose of 20 mg BID.[19] If treatment was well-tolerated after a week at this target dose, the dose was increased to 40 mg BID. However, if the 20 mg dose was not well-tolerated, the dose was decreased to 10 mg.

Efficacy and clinical trials

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.[2] However, post hoc analysis did not demonstrate a statistically significant difference in efficacy between LY-2140023 and olanzapine (positive control) groups. 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.

A second randomized, double-blind, placebo- and active-controlled clinical trial gave schizophrenia patients various doses (5, 20, 40, or 80 mg) of LY-2140023 monohydrate twice daily, yet none of the four doses were found to be more efficacious than placebo on measures of PANSS total score.[11] 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. Due to the possibility of a heightened placebo response that may have reduced the ability to detect a significant response to the drug across the LY-2140023 and olanzapine groups, clinical studies of the drug's efficacy were continued.[20]

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.[20] Patients receiving LY-2140023 were compared to patients receiving other antipsychotic medications, including olanzapine, risperidone, and aripiprazole, for a 24-week treatment phase and optional 28-week extension phase. Researchers found that over the initial 6–8 weeks of treatment, the improvement on the PANSS did not differ between groups. At later time points, it was found that the groups receiving the antipsychotic medications showed significantly greater improvement than the LY-2140023 group.

Tolerability and side effects

LY-2140023 has generally been found to be safe and tolerable. 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.[2] No clinically significant changes in vital signs or worsening of extrapyramidal symptoms were reported in association with LY-2140023 use during an initial phase II clinical trial.[2][11] However, a second, multicenter study reported four patients experiencing convulsions, suggesting a potential for increased risk of seizures during treatment. 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.[20]

Mild weight loss has also been associated with LY-2140023. In patients receiving 40 mg twice daily, a 0.51 kg weight reduction was observed after 4 weeks of treatment.[2]

Eli Lilly stops phase III development

In August 2012, Eli Lilly and Company announced their decision to stop their ongoing clinical studies investigating LY-2140023 as a treatment for schizophrenia after their phase II study did not meet its primary endpoint.[21] The company completed a phase II, randomized, double-blind, placebo- and active-controlled, parallel-group-assignment, dose-ranging, inpatient, multi-center clinical trial.[22] Patients were randomized to receive 5, 20, 40, or 80 mg of LY-2140023, placebo, or olanzapine for 28 days. Results of the clinical trial indicated that neither LY-2140023 nor olanzapine were significantly more efficacious than the placebo as determined with PANSS total scores. Post hoc analyses indicated only a trend towards improvement with LY-2140023, while olanzapine was associated with a significant improvement in total PANSS total score. 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”.[21]

References

  1. 1 2 3 4 5 6 7 8 9 10 11 Rorick-Kehn LM, Johnson BG, Burkey JL, Wright RA, Calligaro DO, Marek GJ, Nisenbaum ES, Catlow JT, Kingston AE, Giera DD, Herin MF, Monn JA, McKinzie DL, Schoepp DD (April 2007). "Pharmacological and pharmacokinetic properties of a structurally novel, potent, and selective metabotropic glutamate 2/3 receptor agonist: in vitro characterization of agonist (−)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic acid (LY404039)". The Journal of Pharmacology and Experimental Therapeutics 321 (1): 308–17. doi:10.1124/jpet.106.110809. PMID 17204749.
  2. 1 2 3 4 5 6 7 8 9 10 Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, Avedisova AS, Bardenstein LM, Gurovich IY, Morozova MA, Mosolov SN, Neznanov NG, Reznik AM, Smulevich AB, Tochilov VA, Johnson BG, Monn JA, Schoepp DD (September 2007). "Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial". Nature Medicine 13 (9): 1102–7. doi:10.1038/nm1632. PMID 17767166.
  3. ↑ Lebois EP (2008). "Neither typical nor atypical: LY404039 provides proof of concept that selective targeting of mGluR2/3 receptors is a valid mechanism for obtaining antipsychotic efficacy". Current Topics in Medicinal Chemistry 8 (16): 1480–1. doi:10.2174/156802608786264209. PMID 19006848.
  4. ↑ Fraley ME (June 2009). "Positive allosteric modulators of the metabotropic glutamate receptor 2 for the treatment of schizophrenia". Expert Opinion on Therapeutic Patents 19 (9): 1259–75. doi:10.1517/13543770903045009. PMID 19552508.
  5. ↑ Strike three: Bad data bury Eli Lilly's late-stage schizophrenia drug
  6. ↑ – Treatment of Schizophrenia
  7. ↑ Stauffer, VL; Millen, BA; Andersen, S; Kinon, BJ; Lagrandeur, L; Lindenmayer, JP; Gomez, JC (September 2013). "Pomaglumetad methionil: No significant difference as an adjunctive treatment for patients with prominent negative symptoms of schizophrenia compared to placebo". Schizophrenia Research 150 (2): 434–441. doi:10.1016/j.schres.2013.08.020. PMID 24035403.
  8. ↑ MRC (Medical Research Council), Glutamate receptors: Structures and functions., University of Bristol Centre for Synaptic Plasticity (2003). Retrieved January 20, 2008.
  9. ↑ Seeman, Phillip, Gua, Hong-Chang (2009). "Glutamate Agonist LY404,039 for Treating Schizophrenia Has Affinity for the Dopamine D2 High Receptor" (PDF). SYNAPSE 63: 935–939. doi:10.1002/syn.20704.
  10. 1 2 3 4 5 Mezler, M., Geneste, H., Gault, L., & Marek, G. J. (2010). "LY-2140023, a prodrug of the group II metabotropic glutamate receptor agonist LY-404039 for the potential treatment of schizophrenia.". Curr Opin Investig Drugs 11 (7): 833–845. PMID 20571979.
  11. 1 2 3 4 5 6 7 Kinon BJ, Gómez JC. (2013). "Clinical development of pomaglumetad methionil: a non-dopaminergic treatment forschizophrenia.". Neuropharmacology 66: 82–86. doi:10.1016/j.neuropharm.2012.06.002. PMID 22722029.
  12. ↑ Seeman, P. (2013). "An agonist at glutamate and dopamine D2 receptors.". Neuropharmacology 66: 87–88. doi:10.1016/j.neuropharm.2012.07.001.
  13. 1 2 3 4 5 6 James A. Monn , Steven M. Massey , Matthew J. Valli , Steven S. Henry , Gregory A. Stephenson ,Mark Bures , Marc Hérin , John Catlow , Deborah Giera , Rebecca A. Wright , Bryan G. Johnson ,Sherri L. Andis , Ann Kingston , and Darryle D. Schoepp (2007). "Synthesis and Metabotropic Glutamate Receptor Activity of S-Oxidized Variants of (−)-4-Amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate: Identification of Potent, Selective, and Orally Bioavailable Agonists for mGlu2/3 Receptor". Journal of Medicinal Chemistry 50 (2): 233–240. doi:10.1021/jm060917u. PMID 17228865.
  14. ↑ Rorick-Kehn LM, Johnson BG, Knitowski KM, Salhoff CR, Witkin JM, Perry KW, Griffey KI, Tizzano JP, Monn JA, McKinzie DL, Schoepp DD (July 2007). "In vivo pharmacological characterization of the structurally novel, potent, selective mGlu2/3 receptor agonist LY404039 in animal models of psychiatric disorders". Psychopharmacology 193 (1): 121–36. doi:10.1007/s00213-007-0758-3. PMID 17384937.
  15. 1 2 McKinzie, D. L., Fell, M. J., Johnson, B. G., Knitowski, K. M., Perry, K. W., Anderson, W. H., ... & Monn, J. A. (March 2011). "Synergistic interactions of the mGlu2/3 receptor agonist LY404039 with antipsychotic agents in behavioral and neurochemical animal models predictive of antipsychotic efficacy.". Schizophrenia Bulletin 37: 110–110. doi:10.1093/schbul/sbq173.
  16. ↑ Norman P. (April 24, 2008). "Medicinal chemistry in eastern England - 19th Symposium, Hatfield, UK". IDDB MEETING REPORT.
  17. ↑ Eli Lilly and Company - Lilly Announces Inconclusive Phase II Study Results for mGlu2/3 at the International Congress on Schizophrenia Research, Eli Lilly, 29 March 2009
  18. ↑ Monn, J. A., Britton, T. C., Valli, M. J., Massey, S. M., Henry, S. S., De Dios, A. (January 2005). "Discovery of LY2140023, a peptide prodrug of the mGlu2/3 receptor agonist LY404039". Neuropharmacology 49: 258–259. doi:10.1016/j.neuropharm.2005.06.013.
  19. ↑ Stauffer, VL; Millen, BA; Andersen, S; Kinon, BJ; Lagrandeur, L; Lindenmayer, JP; Gomez, JC (September 2013). "Pomaglumetad methionil: No significant difference as an adjunctive treatment for patients with prominent negative symptoms of schizophrenia compared to placebo". Schizophrenia Research 150 (2): 434–441. doi:10.1016/j.schres.2013.08.020. PMID 24035403.
  20. 1 2 3 Adams, D. H., Kinon, B. J., Baygani, S., Millen, B. A., Velona, I., Kollack-Walker, S., & Walling, D. P. (2013). "A long-term, phase 2, multicenter, randomized, open-label, comparative safety study of pomaglumetad methionil (LY2140023 monohydrate) versus atypical antipsychotic standard of care in patients with schizophrenia.". BMC Psychiatry 13 (1): 143. doi:10.1186/1471-244X-13-143. PMC 3666887. PMID 23694720.
  21. 1 2 Eli Lilly and Company -Lilly Stops Phase III Development of Pomaglumetad Methionil For the Treatment of Schizophrenia Based on Efficacy Results, Eli Lilly, 29 August 2012
  22. ↑ NCT00520923: Eli Lilly & Co CLINICALTRIALS.GOV -NCT00520923: A study for patients with schizophrenia. Eli Lilly & Co CLINICALTRIALS.GOV 2007, Stauffer et al., ClinicalTrials.gov
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