Pomaglumetad

Pomaglumetad
Clinical data
ATC code
  • none
Legal status
Legal status
  • US: Not FDA-approved
Identifiers
  • (−)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC7H9NO6S
Molar mass235.21 g·mol−1
3D model (JSmol)
  • C1[C@]([C@@H]2[C@H]([C@@H]2S1(=O)=O)C(=O)O)(C(=O)O)N
  • 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
 ☒NcheckY (what is this?)  (verify)

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.[1] Pharmacological research has focused on its potential antipsychotic and anxiolytic effects. Pomaglumetad 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 pomaglumetad have focused on the prodrug LY-2140023, a methionine amide of pomaglumetad (also called pomaglumetad methionil) since pomaglumetad exhibits low oral absorption and bioavailability in humans.[2]

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

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".[8]

  1. ^ Rorick-Kehn LM, Johnson BG, Burkey JL, Wright RA, Calligaro DO, Marek GJ, et al. (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): 308–317. doi:10.1124/jpet.106.110809. PMID 17204749. S2CID 23666836.
  2. ^ a b c Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, et al. (September 2007). "Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial". Nature Medicine. 13 (9): 1102–1107. doi:10.1038/nm1632. PMID 17767166. S2CID 6417333.
  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): 1480–1481. doi:10.2174/156802608786264209. PMID 19006848.
  4. ^ Fraley ME (September 2009). "Positive allosteric modulators of the metabotropic glutamate receptor 2 for the treatment of schizophrenia". Expert Opinion on Therapeutic Patents. 19 (9): 1259–1275. doi:10.1517/13543770903045009. PMID 19552508. S2CID 23242384.
  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 (November 2013). "Pomaglumetad methionil: no significant difference as an adjunctive treatment for patients with prominent negative symptoms of schizophrenia compared to placebo". Schizophrenia Research. 150 (2–3): 434–441. doi:10.1016/j.schres.2013.08.020. PMID 24035403. S2CID 27953077.
  8. ^ Philippidis, Alex (3 March 2015). "Denovo Licenses Failed Schizophrenia Candidate from Lilly". Genetic Engineering & Biotechnology News (Paper, vol 35, i 7, pg 12). Retrieved 2016-06-10. Lilly has an option to reacquire pomaglumetad upon a successful clinical trial.