LY-404,039

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LY-404,039
LY404039 structure.png
Systematic (IUPAC) name
(-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid
Clinical data
Legal status ?
Identifiers
CAS number  YesY
ATC code ?
PubChem CID 9834591
Chemical data
Formula C7H9NO6S 
Mol. mass 235.214 g/mol
 YesY (what is this?)  (verify)

LY-404,039 is a drug used in scientific research that acts as a selective agonist for the metabotropic glutamate receptor group II subtypes mGluR2 and mGluR3.[1] A study shows considerable affinity (Ki = 8.2±1nM) for the D2High receptor as well, proposing a possible mechanism of action.[2] It has anxiolytic and antipsychotic effects in animal studies, but without causing sedation.[3]

Early human trials using a prodrug form of LY-404,039 called pomaglumetad methionil (LY-214,0023 monohydrate) have also given encouraging results.[4][5][6] A trial in 2009 failed to prove superiority over placebo or Olanzapine, but Lilly explained this as being due to an exceptionally high placebo response.[7] Eli Lilly terminated further development of the compound in 2012 after it failed in phase III clinical trials.[8][9] In September 2013 the results of a randomised placebo-controlled clinical trial investigating the impact of adjunctive pomaglumetad methionil on prominent negative symptoms in schizophrenia was published and failed to demonstrate any benefit from adjunctive pomaglumetad methionil.[10]

Pomaglumetad methionil


See also[edit]

References[edit]

  1. ^ 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. ^ PHILIP SEEMAN AND HONG-CHANG GUA (2009). "Glutamate Agonist LY404,039 for Treating Schizophrenia Has Affinity for the Dopamine D2 High Receptor". SYNAPSE: 935–939. doi:10.1002/syn.20704. 
  3. ^ 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. 
  4. ^ 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. 
  5. ^ 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. PMID 19006848. 
  6. ^ 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. 
  7. ^ 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
  8. ^ Strike three: Bad data bury Eli Lilly's late-stage schizophrenia drug
  9. ^ – Treatment of Schizophrenia
  10. ^ 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.