Comments

1. #1 stumpy

   September 4, 2007

   If the new drug turns out to have fewer adverse effects, maybe they won’t need a depot formulation. On a somewhat related note: I haven’t seen anything yet about the drug’s other receptor affinities — that is, apart from its activity at mGlu2/3. Does anybody have any information on that?

2. #2 Joseph j7uy5

   September 4, 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).
   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.

   Neuroscience Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, DC0510, Indianapolis, IN 46285, USA.

   Group II metabotropic glutamate (mGlu) receptor agonists, including (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740) and (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), have demonstrated efficacy in animal models of anxiety and schizophrenia, and LY354740 decreased anxiety in human subjects. Herein, we report the in vitro pharmacological profile and pharmacokinetic properties of another potent, selective, and structurally novel mGlu2/3 receptor agonist, (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY404039) and provide comparisons with LY354740. Similar to LY354740, LY404039 is a nanomolar potent agonist at recombinant human mGlu2 and mGlu3 receptors (K(i) = 149 and 92, respectively) and in rat neurons expressing native mGlu2/3 receptors (Ki = 88). LY404039 is highly selective for mGlu2/3 receptors, showing more than 100-fold selectivity for these receptors, versus ionotropic glutamate receptors, glutamate transporters, and other receptors targeted by known anxiolytic and antipsychotic medications. Functionally, LY404039 potently inhibited forskolin-stimulated cAMP formation in cells expressing human mGlu2 and mGlu3 receptors. Electrophysiological studies indicated that LY404039 suppressed electrically evoked excitatory activity in the striatum, and serotonin-induced l-glutamate release in the prefrontal cortex; effects reversed by LY341495. These characteristics suggest LY404039 modulates glutamatergic activity in limbic and forebrain areas relevant to psychiatric disorders; and that, similar to LY354740, it works through a mechanism that may be devoid of negative side effects associated with current antipsychotics and anxiolytics. Interestingly, despite the slightly lower potency (approximately 2-5-fold) of LY404039 versus LY354740 in binding, functional, and electrophysiological assays, LY404039 demonstrated higher plasma exposure and better oral bioavailability in pharmacokinetic experiments. Collectively, the current data indicate that LY404039 may be valuable in the treatment of neuropsychiatric disorders, including anxiety and psychosis.

   In vivo pharmacological characterization of the structurally novel, potent, selective mGlu2/3 receptor agonist LY404039 in animal models of psychiatric disorders.
   Rorick-Kehn LM, Johnson BG, Knitowski KM, Salhoff CR, Witkin JM, Perry KW, Griffey KI, Tizzano JP, Monn JA, McKinzie DL, Schoepp DD.

   Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, DC0510, Indianapolis, IN 46285, USA. RorickKehnLM@lilly.com

   RATIONALE: Data from both preclinical and clinical studies have provided proof of concept that modulation of limbic and forebrain glutamate, via mGlu2/3 receptor agonists, might provide therapeutic benefits in many psychiatric disorders including schizophrenia and anxiety. OBJECTIVE: The aim of this study was to assess the efficacy of a structurally novel, potent, selective mGlu2/3 receptor agonist with improved bioavailability (LY404039) in animal models predictive of antipsychotic and anxiolytic efficacy. MATERIALS AND METHODS: LY404039 was assessed in amphetamine- and phencyclidine-induced hyperlocomotion, conditioned avoidance responding, fear-potentiated startle, marble burying, and rotarod behavioral tests. Monoamine release and turnover were assessed using microdialysis and ex vivo tissue levels. RESULTS: LY404039 attenuated amphetamine- and phencyclidine-induced hyperlocomotion (3-30 and 10 mg/kg, respectively). LY404039 (3-10 mg/kg) inhibited conditioned avoidance responding. LY404039 also reduced fear-potentiated startle in rats (3-30 microg/kg) and marble burying in mice (3-10 mg/kg), indicating anxiolytic-like effects. Importantly, LY404039 did not produce sedative effects or motor impairment as measured by rotarod performance and lack of escape failures in the conditioned avoidance task (at doses up to 30 and 10 mg/kg, respectively). LY404039 (10 mg/kg) also increased dopamine and serotonin release/turnover in the prefrontal cortex. CONCLUSIONS: These results demonstrate the broad preclinical efficacy of LY404039 across multiple animal models of antipsychotic and anxiolytic efficacy. Additionally, this compound modulates mesocortical neurotransmission and provides a novel mechanism for the treatment of psychiatric disorders that may be associated with improved efficacy and reduced incidence of undesirable side effects. As glutamatergic dysfunction has been linked to the etiology of schizophrenia, clinical studies with more potent mGlu2/3 agonists, such as LY404039, may be useful to explore the validity of this hypothesis.

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3. #3 stumpy

   September 4, 2007

   I appreciate this information, but what I’d like to know is, what are the dissociation constants of this new molecule at different receptor types and subtypes? Not to be ungrateful — this is interesting, as far as it goes.

4. #4 Joseph j7uy5

   September 4, 2007

   I think I know what you are getting at: most molecules interact with more than one receptor type, and before we give this to people, we would like to be fully informed about what transmitter systems are going to be affected, not to mention which cytochrome enzymes are going to be affected. I don’t see anything more specific in the public literature.

   If Mark Demitrack is still with Lilly in Indianapolis, he might be willing to open up a little about the specifics. I have to believe they have done a lot of work to characterize their new molecular entity, but they are not openly sharing much of it.

   Last I knew, Mark’s email was madmd (ha ha, Mark A Demitrack, Mad MD) at lilly dot com. But I haven’t been in touch with him since he left the Eating Disorder program. That was what, 12 years ago?

5. #5 stumpy

   September 5, 2007

   It was a long time. Atul Pande went to Lilly too I think. Thanks again for the info.

6. #6 Doc Bushwell

   September 11, 2007

   Nice post, Joseph. Your measured assessment is appreciated, re: the cautiously optimistic outlook on Phase II results. You alluded to depot delivery so I assume you refer to the rapid clearance and relatively short half-life of 404039. There’s no published values for CYP or liver metabolism that I can find, but LY354740 (poorer bioavailability, but longer half-life) looks like it’s cleared unmetabolized through the kidneys. Whether this applies to LY404039, well, I expect the folks at Lilly know.

   stumpy, I’m not sure which “different receptors” you’re referring to, and you may have already found the table from the article Joseph cited, but what the hey, I’ll post it ’cause I can.

   From Rorick-Kehn et al. Pharmacology and Exp. Thearpeutics 2007:

   TABLE 4 Effects of mGlu2/3 receptor agonists at ionotropic glutamate receptors, glutamate transporter subtypes, and monoamine and other receptors

   The Ki was determined for each neurotransmitter receptor or transporter. Data are presented as the mean ? S.E.M. of two to three separate experiments. Where affinities are reported as greater than 1 uM concentration, this was the highest concentration tested that inhibited <50% specific bound radiolabel in the assay.

   Ki or IC50 values are expressed in micromolar; first column is LY354740 & the second is LY404039. – Doc Bushwell

   iGluR ligand (Ki)
   [3H]CGP 39653 (NMDA) >100 >100
   [3H]AMPA >100 >100
   [3H]Kainate >100 >100
   Transporter subtype (IC50)
   Rat EAAT1 >5 >5
   Rat EAAT2 >5 >5
   Rat EAAT3 >5 >5
   Monoamine ligand (Ki)
   Dopamine, D1 >100 >10
   Dopamine, D2 >100 >10
   Serotonin, 5-HT2 >100 >10
   Adrenergic (Ki)
   1-Adrenergic >100 >10
   2-Adrenergic >100 >10
   -Adrenergic >100 >10
   Miscellaneous (Ki)
   Histamine, H1 >100 >10
   Benzodiazepine >100 >10
   GABAA >100 >10
   Muscarinic >100 >10

7. #7 George

   August 30, 2008

   But is this drug out on the market and if so-how much does it cost?

8. #8 Joseph j7uy5

   August 30, 2008

   The drug is not yet available. I realize now that I did not mention that fact, thinking it was obvious. But the reasons it is obvious are not obvious. For one, the name LY404039 is an indication that the drug is still under investigation. Once it is available to the general public, it will have a flashy name, rather than a number. The other clue is that these were phase II studies. There are three phases that have to be done before a drug is submitted for approval.

   So, it is “obvious” only if you happy to know those things, which most people will not know.

   I will try to remember to be more clear next time.

9. #9 Jim Stewart

   August 31, 2009

   Does anyone know when the phase III will be completed? My daughter is schizophrenic. We are still trying to find a medication to stabilize her. thanks

10. #10 Joseph j7uy5

    September 1, 2009

    Lilly’s site lists it as still being in Phase II as of 1 July, 2009. There is no way of knowing when or if it will progress to phase III.