Abstract
MGS0274 besylate is an ester‐based lipophilic prodrug of a metabotropic glutamate (mGlu) 2 and mGlu3 receptor agonist MGS0008 and being developed for the treatment of schizophrenia. We investigated the disposition of these compounds in rats and monkeys and in vitro metabolism in humans to evaluate whether MGS0274 besylate could be useful as a prodrug in humans. After the oral administration of MGS0274 besylate to monkeys (2.89 mg/kg), MGS0008 was immediately found in plasma, reached a maximum concentration at 4 hours postdose, and decreased with a terminal half‐life of 16.7 hours; MGS0274 was barely detectable. The oral bioavailability as MGS0008 was 83.7%, which was approximately 20‐fold greater than that after oral dosing of MGS0008 (3.8%). In rats, MGS0008 penetrated the cerebrospinal fluid and was eliminated slower than from plasma. The in vitro metabolism study indicated that MGS0274 was rapidly hydrolyzed to MGS0008, which was not further metabolized. After the intravenous administration of MGS0008 to rats and monkeys, almost all the dose was excreted unchanged in urine. These results suggested that MGS0274 was, as expected, presystemically hydrolyzed to MGS0008 after gastrointestinal absorption and that MGS0008 was distributed throughout the body without further metabolism and ultimately excreted in urine in the animals. Furthermore, the hydrolytic activity against MGS0274 in the human liver S9 fraction was comparable to that in monkeys, suggesting the possibility of the rapid presystemic hydrolysis of MGS0274 to MGS0008 in humans, as it is in monkeys. Consequently, MGS0274 besylate is expected to function as a preferable prodrug in humans.
Highlights
Group II metabotropic glutamate (mGlu) receptors play a role in regulating gluta‐ matergic tone in the forebrain and limbic area, where glutamater‐ gic dysregulation has been reported in patients with schizophrenia, and agonists for mGlu2/3 receptors are thought to be beneficial for the treatment of schizophrenia.[6,28,29] LY2140023 discovered by Eli Lilly and Company, which is an orally bioavailable prodrug of the mGlu2/3 receptor agonist LY404039 (Figure 1), significantly improved positive and negative symptoms of schizophrenia in a phase 2 proof‐of‐concept trial, compared with placebo.[31]
Group II mGlu receptors play a role in regulating gluta‐ matergic tone in the forebrain and limbic area, where glutamater‐ gic dysregulation has been reported in patients with schizophrenia, and agonists for mGlu2/3 receptors are thought to be beneficial for the treatment of schizophrenia.[6,28,29]
A post hoc analysis of data from phase 2 and phase 3 clinical trials for LY2140023 indicated that the patients with schizophrenia who had been ill for 3 years or less or previously treated with a dopamine D2 receptor antagonist exhib‐ ited the therapeutic response to LY2140023.19 the potential of mGlu2/3 receptors and their agonists as therapeutic targets and medications for schizophrenia is still worth investigating
Summary
Group II mGlu (mGlu2/3) receptors play a role in regulating gluta‐ matergic tone in the forebrain and limbic area, where glutamater‐ gic dysregulation has been reported in patients with schizophrenia, and agonists for mGlu2/3 receptors are thought to be beneficial for the treatment of schizophrenia.[6,28,29] LY2140023 discovered by Eli Lilly and Company, which is an orally bioavailable prodrug of the mGlu2/3 receptor agonist LY404039 (Figure 1), significantly improved positive and negative symptoms of schizophrenia in a phase 2 proof‐of‐concept trial, compared with placebo.[31]. KINOSHITA et al receptor were associated with a change in the positive and neg‐ ative syndrome scale, suggesting a pharmacogenetic relationship between the single nucleotide polymorphisms and the response to LY2140023 treatment.[21] In addition, a post hoc analysis of data from phase 2 and phase 3 clinical trials for LY2140023 indicated that the patients with schizophrenia who had been ill for 3 years or less or previously treated with a dopamine D2 receptor antagonist exhib‐ ited the therapeutic response to LY2140023.19 the potential of mGlu2/3 receptors and their agonists as therapeutic targets and medications for schizophrenia is still worth investigating. Based on the similarities in the chemical structures of MGS0008, LY354740, and LY404039, the possibility that MGS0008 might exhibit poor oral bioavailability in humans was predicted Efforts to overcome this limitation were deemed vital for the future success of the clinical development of MGS0008. The results indicate that MGS0274 besylate is expected to function properly as a prodrug in humans
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