mGlu2 Receptor (Ki = 149 nM); hmGluR3 (Ki = 92 nM)

In rats with neurons expressing native mGlu2/3 receptors (Ki=88 nM), Pomaglumetad/LY404039 is a nanomolar potent agonist [1]. Functioning as a potent inhibitor of forskolin-stimulated cAMP formation, LY404039 acts on cells that express human mGlu2 (EC50=23 nM) and mGlu3 (EC50=48 nM) receptors [1]. According to electrophysiological research, LY404039 suppresses serotonin-induced L-glutamate release in the prefrontal cortex and electrically evoked excitatory activity in the striatum. LY404039 exhibits a maximum inhibition of 85.6% at 1 μM, effectively suppressing the frequency of 5-HT-induced excitatory postsynaptic currents (EPSC) with an EC50 of 82.3 nM [1]. LY404039 blocks the human cloned D2 receptor from binding to the D2-specific antagonist [3H]domperidone, with a dissociation constant of 8.2 nM for high D2 and 1640 nM for low D2. The dissociation constants of LY404039 were determined using rat striatal tissue, and they were 12.6 nM at D2 high and 2100 nM at D2 low [2].

---

Similar to LY354740, Pomaglumetad/LY404039 is a nanomolar potent agonist at recombinant human mGlu2 and mGlu3 receptors (Ki = 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. [1]

---

The dissociation constants of 8.2 nM and 12.6 nM for Pomaglumetad/LY404039 at D2High (which is the functional state for D2; Seeman, 2006), is lower than the dissociation constants of 92 nM–149 nM for LY404039 at the human metabotropic-2 and -3 glutamate receptors (Rorick-Kehn et al., 2007), indicating that D2High receptors would be occupied at clinical doses that occupy the glutamate receptors.

LY404039/Pomaglumetad reduces hyperkinesis brought on by amphetamines (3–30 mg/kg) and phencyclidines (10 mg/kg), respectively. The conditioned avoidance responses are inhibited by LY404039 (3–10 mg/kg). Additionally, marble burying in mice (3–10 mg/kg) and fear-potentiated startle in rats (3–30 μg/kg) are both decreased by LY404039, indicating anxiolytic-like effects. Additionally, LY404039 (10 mg/kg) enhances serotonin and dopamine release/turnover in the prefrontal cortex [3]. Exposure increased proportionately with the dose after LY404039 was given orally to fasting rats at doses of 1, 3, or 10 mg/kg. In rats treated with LY404039 (10 mg/kg; po), the Cmax was 1528.5 ng/mL and the Tmax was 2 hours [1].

---

Objective: The aim of this study was to assess the efficacy of a structurally novel, potent, selective mGlu2/3 receptor agonist with improved bioavailability (Pomaglumetad/LY404039) in animal models predictive of antipsychotic and anxiolytic efficacy.
Materials and methods: Pomaglumetad/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: Pomaglumetad/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 Pomaglumetad/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. [3]

Receptor Binding Assays. [1]
Cell lines expressing human mGlu2, mGlu3, mGlu1a, mGlu5a, mGlu4a, mGlu6, mGlu7a, and mGlu8 receptors were derived as described previously (Schoepp et al., 1997) and cultured in Dulbecco’s modified Eagle’s medium with 5% dialyzed fetal bovine serum, 1 mM glutamine, 1 mM sodium pyruvate, 50 mg/ml Geneticin, and 0.2 mg/ml hygromycin B. Confluent cultures were passaged weekly. These cells are referred to as rat glutamate transporter (RGT)...

Male Sprague–Dawley rats weighing between 200–350 g were tested in the locomotor, fear-potentiated startle, microdialysis/monoamine turnover, and rotarod experiments. The sample sizes for each experiment were as follows: Pomaglumetad/LY404039 effects on spontaneous locomotor activity, n = 10 per group; clozapine effects on spontaneous locomotor activity, n = 6–8/group; LY404039 effects on amphetamine-induced hyperlocomotion, n = 11–12 per group; reversal of LY404039 effects on amphetamine-induced hyperlocomotion, n = 10–12 per group; fear-potentiated startle, n = 8 per group; LY341495 reversal of fear-potentiated startle effects, n = 12 per group; microdialysis experiments, n = 5; ex vivo tissue analysis, n = 8 per group; rotarod performance, n = 8 per group; PCP-induced disruptions of rotarod performance n = 8 per group. For the locomotor activity and fear-potentiated startle experiments, rats were pair-housed and food-fasted for 12 to 18 h before the experiment, with water available ad libitum. The acute fasting procedures were routinely implemented to ensure more consistent drug exposure across the various dose groups and experiments. For the microdialysis experiments, rats were single-housed with standard laboratory chow and water available ad libitum. To allow the implantation of dialysis probes, rats were anesthetized with chloral hydrate/pentobarbital (170 and 36 mg/kg in 30% propylene glycol and 14% ethanol, respectively). After surgery, rats were single-housed to avoid interference with the chronically implanted dialysis probe of the cagemate. For all other experiments, rats were pair-housed with standard laboratory chow and water available ad libitum. All animals were maintained on a 12-h light/dark cycle (lights on at 06:00). [3]

---

Male Fischer-F344 rats, weighing between 350–400 g, were tested in the conditioned avoidance responding experiment (n = 6). The rats used in this experiment had previous exposure to drug treatments before receiving Pomaglumetad/LY404039. A washout period of 1 week was implemented before the LY404039 experiment. Rats were pair-housed with water and standard laboratory chow available ad libitum. Male NIH Swiss mice, weighing approximately 28–32 g, were tested in the rotarod and marble-burying experiments (Pomaglumetad/LY404039 or chlordiazepoxide, n = 6; vehicle, n = 12). For these experiments, mice were group-housed (n = 10–12 per cage) with water and laboratory chow available ad libitum. [3]

---

Spontaneous locomotor activity [3]
To assess the effects of Pomaglumetad/LY404039 and clozapine on spontaneous locomotor activity, animals received an oral gavage of vehicle (sterile water, 1 ml/kg), LY404039 (0.3, 1, 3, or 10 mg/kg), or clozapine (0.3, 1, 3, or 10 mg/kg) and returned to their home cage. After 60 min, rats were placed in the test cage for a 45-min assessment of spontaneous locomotor activity.

---

Amphetamine-induced hyperlocomotion [3]
Rats were administered a randomly assigned dose of Pomaglumetad/LY404039 (0.3, 1, 3, 10, or 30 mg/kg, p.o.) or sterile water vehicle (1 ml/kg, p.o.) and returned to their home cage for 30 min. Rats were then placed in the test cage for a 30-min habituation period to allow for acclimation to the test cage environment and to measure baseline locomotor activity. After the habituation period, animals received a challenge dose of amphetamine (3 mg/kg, s.c.) or 0.9% NaCl vehicle (1 ml/kg, s.c.) and then observed for an additional 60 min. The effect of the benzodiazepine anxiolytic diazepam on PCP-induced hyperlocomotion was also assessed. For this experiment, animals received diazepam (1, 3, 10, or 30 mg/kg, p.o.) or sterile water vehicle (1 ml/kg, p.o.) and were returned to their home cage for 30 min as described for LY404039. After the 30-min habituation period, rats received a challenge dose of PCP (5 mg/kg, s.c.) or 0.9% NaCl vehicle (1 ml/kg, s.c.) and were observed for 60 min.

---

Reversal of Pomaglumetad/LY404039 suppression of PCP- and amphetamine-induced hyperlocomotion [3]
Rats were administered LY341495 (1 mg/kg, s.c.) or 0.9% NaCl vehicle (1 ml/kg, s.c.) and were returned to their home cage for 90 min. The parameters used in this experiment were chosen based on PCP time-course analysis, which determined that LY404039 was most potent at reducing PCP-induced behaviors at 1–2 h post-administration (see below). Rats received an injection of LY404039 (10 mg/kg, p.o.) or sterile water vehicle (1 ml/kg, p.o.) and tested for activity levels during a 30-min habituation period. After the 30-min habituation period, a challenge dose of amphetamine (3 mg/kg, s.c.), PCP (5 mg/kg, s.c.), or 0.9% NaCl vehicle (1 ml/kg, s.c.) was delivered, and rats were observed for an additional 60 min.

---

Onset and duration of action studies [3]
Onset and duration of action studies were carried out using a time-sampling procedure in which the time between dosing (Pomaglumetad/LY404039, 10 mg/kg, p.o.) and experimental testing was systematically varied. The pretreatment times tested were: 1, 2, 3, 4, 8, and 24 h. Animals in the vehicle/vehicle group were distributed evenly across all drug pretreatment groups. All other procedures were as described above.

---

Rats were trained until performance was consistently above 90% avoidance responding (45 avoidance responses out of 50 trials). Drug treatments began once the rats performed greater than 90% avoidance responses on three consecutive days. On the day before each drug day, rats received a sham injection of vehicle 30 min before the session (vehicle day). If rats reached criterion on the vehicle day (greater than 90% avoidance), drug treatments were administered on the following day. On drug days, Pomaglumetad/LY404039 (3 or 10 mg/kg, i.p.) was administered 30 min before the session. [3]

---

For the dose-response assessment of fear-potentiated startle, rats received Pomaglumetad/LY404039 (0.03, 0.3, 3, or 30 μg/kg, p.o.), diazepam (0.6 mg/kg, p.o.), or sterile water vehicle (1 ml/kg, p.o.) 30 min before the session. In a separate group of animals, rats received vehicle (1 ml/kg, p.o.), LY404039 (30 μg/kg, p.o.), LY341495 (1 mg/kg, s.c.), or LY404039 (30 μg/kg, p.o.) + LY341495 (1 mg/kg, s.c.) on testing day 3. For this experiment, LY404039 was administered 30 min before the startle session, and LY341495 was administered 60 min before the startle session.

---

Onset and duration of action studies [3]
Onset of action and duration of action studies were carried out by varying the time between dosing (Pomaglumetad/LY404039, 30 μg/kg, p.o.) and experimental testing. The pretreatment times tested were: 1, 2, 4, 8, and 24 h. All other procedures were as described above.

---

Marble burying and rotarod performance in mice [3]
Before the marble-burying experiment, the effects of Pomaglumetad/LY404039 and chlordiazepoxide on motor performance were evaluated using a rotarod apparatus. Mice were acclimated to a dimly lit testing room for 60 min and then dosed with LY404039 (1, 3, or 10 mg/kg, i.p.), chlordiazepoxide (3, 10, or 30 mg/kg, i.p.), or vehicle (physiological saline, 10 ml/kg, i.p.) and returned to their home cage. Thirty minutes later, mice were placed on a rotarod (Ugo Basile, Comerio VA, Italy) operating at a speed of 6 rpm and observed for falling. Mice that fell off the rotarod on two occasions during 2 min were scored as failing. Immediately after the rotarod test, anxiolytic-like effects were evaluated in the marble-burying test. For this test, mice were placed in a plastic chamber (17 × 28 × 12 cm) containing sawdust shavings (5 mm depth) and 20 blue marbles (1.5 cm diameter) located on top of the shavings. The number of marbles buried (2/3 covered with sawdust) was recorded after 30 min. All mice were included in the marble-burying experiment regardless of performance in the rotarod test.

---

Rat rotarod performance [3]
An automated rotarod apparatus tested for motor impairment and ataxia. Ninety minutes before drug administration, rats were trained to stay on the rotarod, rotating at 4 rpm, over four successive trials. Those rats that remained on the rod for consecutive 60-s periods were retested 30 min before drug administration. Rats successful in the retesting session received Pomaglumetad/LY404039 (3, 10, or 30 mg/kg, p.o.) or sterile water vehicle (1 ml/kg, p.o.). Thirty minutes later, rats were again tested on the rotarod for a period of up to 60 s. Data were expressed as the number of seconds the animal remained on the rotarod apparatus.

An additional experiment was conducted to determine the interaction between PCP and Pomaglumetad/LY404039. Experimental procedures were identical to those described above. For this experiment, rats were given injections of PCP (1, 2, 3, 5, or 8 mg/kg, s.c.) or 0.9% NaCl vehicle (1 ml/kg, s.c.) 30 min before administration of LY404039 (3 or 10 mg/kg, p.o.) or sterile water vehicle (1 ml/kg, p.o.).

---

Tissue levels of monoamines and monoamine metabolites in the prefrontal cortex [3]
Rats were removed from their home cages and injected s.c. with 10 mg/kg Pomaglumetad/LY404039, 10 mg/kg clozapine, or 0.9% NaCl vehicle and returned to their cages. For the initial experiments, rats were removed after 30 min and killed via decapitation in an adjacent room. For the time-course experiments, rats were removed and decapitated 0.5, 1, 2, 4, or 24 h post-injection. The prefrontal cortex was dissected out and frozen on dry ice. The tissue samples were then weighed individually and stored at −80°C in plastic tubes containing 0.5 ml of 0.01 M HCl until analyzed for DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-HT, and 5-HIAA. Immediately before analysis, samples were thawed at room temperature, and 0.4 ml of 0.01 M HCl (containing isoproterenol as an internal standard) was added. After sonication, 100 μl of 1.5 M perchloric acid was added, and the samples were vortexed and stored at 4°C for 30 min. The samples were then centrifuged for 2 min at 12,000 rpm, and the supernatant was analyzed by HPLC with electrochemical detection.

---

Dissolved in 0.9% saline and the pH is adjusted to 6.0 with 1 M NaOH; 10 mg/kg; i.p. injection

Separate mGlu2 and mGlu3 receptor knockout mice are established

LY404039/Pomaglumetad demonstrated higher plasma exposure and better oral bioavailability in pharmacokinetic experiments. [1]

---

Due to the poor oral bioavailability of previous generation mGlu2/3 receptor agonists, we discovered LY404039/Pomaglumetad, a novel agent with improved potency and bioavailability (Monn et al. 2007) that represents a potentially viable clinical investigational tool. [3]

[1]. 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). J Pharmacol Exp Ther. 2007 Apr;321(1):308-17.

[2]. Seeman P. An agonist at glutamate and dopamine D2 receptors, LY404039. Neuropharmacology. 2013 Mar;66:87-8.

[3]. In vivo pharmacological characterization of the structurally novel, potent, selective mGlu2/3 receptor agonistLY404039 in animal models of psychiatric disorders. Psychopharmacology (Berl). 2007 Jul;193(1):121-36.

LY404039/Pomaglumetad is an organic heterobicyclic compound that is (1S,5R)-2-thiabicyclo[3.1.0]hexane carrying oxo, oxo, amino, carboxy, and carboxy groups at positions 2, 2, 4S, 4S, and 6S, respectively. It is a potent agonist of group II metabotropic glutamate receptors mGluR2 mGluR3 (Ki = 149 nM and 92 nM, respectively) and exhibits antipsychotic and anxiolytic efficacy in animal models. It has a role as a metabotropic glutamate receptor agonist, an antipsychotic agent, an anxiolytic drug and a dopamine agonist. It is a dicarboxylic acid, a bridged compound, an organic heterobicyclic compound, a sulfone and a non-proteinogenic amino acid derivative.

---

Receptor Binding Assays. Group II mGlu receptor binding affinities for LY354740 and Pomaglumetad/LY404039 were determined by displacement of specific [3H]LY341495 binding in RGT cells expressing recombinant human mGlu2 and mGlu3 receptor subtypes and in cortical tissue prepared from rat forebrain under conditions selectively labeling group II mGlu receptors. As shown in Table 2 and Fig. 2, both LY354740 and LY404039 displaced [3H]LY341495 binding with nanomolar potencies: (LY354740: mGlu2, Ki = 99 ± 7 nM;
The current report details the in vitro pharmacological and pharmacokinetic profile of a structurally novel group II metabotropic glutamate receptor agonist Pomaglumetad/LY404039. We report here that, similar to LY354740 (Schoepp et al., 1997), LY404039 is a nanomolar potent agonist at recombinant human mGlu2/3 receptors and in rat neurons expressing native mGlu2/3 receptors. Also similar to LY354740, LY404039 is highly selective for mGlu2/3 receptors, showing virtually no affinity for group I or group III... [1]

---

The clinical data show that 80 mg of Pomaglumetad/LY404039 twice per day did not reduce the clinical symptoms more than the placebo, while the comparator drug olanzapine reduced the positive symptoms and the negative signs (Kinon et al., 2011; Seeman, 2012). The dissociation constant of 8.2 nM at the D2High receptor indicates that LY404039 is weaker than aripiprazole, which has a dissociation constant of 0.2 nM at D2High (Seeman, 2008). Nevertheless, LY404039 may act as a partial agonist. In discussions on LY404039, it is essential to avoid comparisons with the pharmacology of related LY congeners, because of the different selectivities that each drug has for various receptors. Finally, it should be noted that the removal of the metabotropic-2 or -3 glutamate receptors leads to behavioural and biochemical dopamine supersensitivity (Seeman et al., 2009), indicating that an underactive glutamate neurotransmission is intimately associated with dopamine hyperactivity. [2]

---

LY404039/Pomaglumetad resulted from an effort to discover selective, potent, orally active mGlu2/3 receptor agonists for the treatment of psychiatric disorders. In this paper, we demonstrated that oral administration of LY404039 produced antipsychotic- and anxiolytic-like effects in several animal models and increased monoamine turnover and release in the prefrontal cortex at lower oral doses than those previously reported for LY354740. Specifically, while LY354740 failed to reverse PCP-induced hyperlocomotion at oral doses up to 100 mg/kg (Rorick-Kehn et al. 2006), LY404039 was effective at doses as low as 1 mg/kg when administered orally (Monn et al. 2007). Using another model of schizophrenia, we report here that LY404039 effectively reversed amphetamine-induced hyperlocomotion at an oral dose of 3 mg/kg. In previous experiments, parenteral routes were required to observe anxiolytic effects with LY354740 (Rorick-Kehn et al. 2006), whereas the current results demonstrate oral anxiolytic-like effects at a dose of 3 μg/kg in the fear-potentiated startle paradigm, demonstrating markedly improved oral potency in vivo. The increased bioavailability observed in rats (63%) relative to LY354740 (~10%; Monn et al. 2007; Johnson et al. 2002) suggests that LY404039 may be an attractive candidate for clinical development in the treatment of neuropsychiatric disorders.

Although not addressed in the current experiments, the relative contribution of mGlu2 versus mGlu3 receptors is an issue that should be examined in future studies, particularly as more selective ligands are discovered. For example, a recent report demonstrated that an mGlu2 receptor potentiator produced behavioral effects similar to those produced by mGlu2/3 receptor agonists in animal models predictive of antipsychotic efficacy, suggesting that mGlu2 receptors may be primarily responsible for the behavioral effects (Galici et al. 2005). Further support is provided by the demonstration that the racemate of LY354740 reversed PCP-induced hyperlocomotion in wild-type, but not mGlu2 receptor knock-out mice (Spooren et al. 2000). Whether the activation of mGlu3 receptors further contributes to the in vivo efficacy of group II mGlu agonists requires further exploration.

Pathological glutamatergic and dopaminergic neurotransmission in limbic and cortical areas is hypothesized to underlie the production of both positive and negative symptoms in schizophrenic patients (Goldman-Rakic 1999; Heresco-Levy 2005). Stress and anxiety disorders are also associated with altered glutamatergic activity in limbic and cortical regions (Bergink et al. 2004; Moghaddam 2002). Many clinically effective antipsychotics are believed to alleviate the positive symptoms of schizophrenia by reducing mesolimbic dopamine release and concomitantly increasing dopamine activity in mesocortical pathways (Goldman-Rakic 1999; Heresco-Levy 2005). However, recent experiments support the contention that the most effective atypical antipsychotics do not work solely through the dopaminergic system, but rather interact through a broad class of neurotransmitter systems (Heresco-Levy 2005; Krystal et al. 2005b). Anxiolytics produce their effects by increasing inhibitory activity in the brain, but a converse approach is to decrease excessive central excitatory activity through modulatory metabotropic glutamatergic mechanisms (Swanson et al. 2005). Described herein is a demonstration of the broad preclinical efficacy of the structurally novel, potent selective mGlu2/3 receptor agonist Pomaglumetad/LY404039. The results also indicate that Pomaglumetad/LY404039 modulates mesocortical glutamatergic and dopaminergic neurotransmission and, in doing so, may provide a novel mechanism for the treatment of psychiatric disorders that is 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 in the clinic. [3]

---

The current treatment of schizophrenia by antipsychotics is based on their ability to interfere with the neurotransmission of dopamine (Seeman, 2006). In fact, the clinical daily doses of antipsychotics and their therapeutic concentrations in the spinal fluid can be precisely predicted by their dissociation constants at the cloned dopamine D2 receptor and by the calculation to occupy between 60% and 80% of the human brain D2 receptors (Seeman, 2006). These data suggest that schizophrenia is associated with a hyperactive neurotransmission of dopamine. It has also been suggested, however, that schizophrenia may be based on an underactive glutamate neurotransmission, based on the observation that phencyclidine, a glutamate antagonist, can elicit temporary psychosis. Based on this hypoglutamate hypothesis, Patil et al. (2007) effectively treated schizophrenia patients with a glutamate receptor agonist, pomaglumetad methionil (LY2140023, the parent substance of which is Pomaglumetad/LY404039). A subsequent clinical trial of LY2140023 on schizophrenia patients, however, was “inconclusive” as to the drug's efficacy (Kinon et al., 2011; see also Kinon and Gómez, 2012). Considering that LY404039 was the first apparently non-dopamine-interfering effective drug for psychosis, it was important to test whether LY404039 was indeed free of anti-dopamine action. It was found that LY404039 inhibited the binding of the D2-specific antagonist, [3H]domperidone, to the human cloned D2 receptor with dissociation constants of 8.2 nM at D2High and 1640 nM at D2Low (Fig. 1; Seeman and Guan, 2009). Using rat striatal tissue, LY404039 had dissociation constants of 12.6 nM at D2High and 2100 nM at D2Low. The addition of guanilylimidodiphosphate eliminated the high-affinity component, consistent with an expected agonist action at the D2 receptor. Moreover, the drug stimulated the incorporation of [35S]GTP-γ-S into the tissue (Fig. 1, bottom), as expected for an agonist. [1]

C7H9NO6S

235.22

235.015

C, 35.75; H, 3.86; N, 5.96; O, 40.81; S, 13.63

635318-11-5

9834591

White to gray solid powder

1.9±0.1 g/cm3

600.3±55.0 °C at 760 mmHg

316.8±31.5 °C

0.0±3.7 mmHg at 25°C

1.661

-2.02

3

7

2

15

451

4

C1[C@]([C@@H]2[C@H]([C@@H]2S1(=O)=O)C(=O)O)(C(=O)O)N

AVDUGNCTZRCAHH-MDASVERJSA-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

(1R,4S,5S,6S)-4-amino-2,2-dioxo-2λ6-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid

LY-404039; LY 404039; 635318-11-5; LY404039; Pomaglumetad; LY-404039; (1R,4S,5S,6S)-4-Amino-2-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid 2,2-dioxide; LY 404039; UNII-531QUG7P9E; 531QUG7P9E; Pomaglumetad;LY404039; LY-404,039; LY404,039; LY 404,039

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: 2 mg/mL (8.50 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication (<60°C).

---

Solubility in Formulation 2: 30% propylene glycol, 5% Tween 80, 65% D5W: 30 mg/mL

---

 (Please use freshly prepared in vivo formulations for optimal results.)