Preclinical disposition of MGS0274 besylate, a prodrug of a potent group II metabotropic glutamate receptor agonist MGS0008 for the treatment of schizophrenia

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.

Safety and pharmacokinetic profiles of MGS0274 besylate (TS‐134), a novel metabotropic glutamate 2/3 receptor agonist prodrug, in healthy subjects

“…18 Since higher exposure of prodrugs causes insufficient exposure of active compounds and might trigger unexpected toxic effects, we synthesized MGS0274 besylate, an ester-based lipophilic prodrug, not only to achieve good gastrointestinal absorption but also to further reduce the systemic exposure to the prodrug itself in humans. 26 In this study, we confirmed that MGS0274 is rapidly absorbed and extensively converted into MGS0008 after dosing of TS-134 in humans, and that the C max and AUC of MGS0008 at steady state increased dose-proportionally over the dose range tested (5-80 mg). receptor, which may achieve sufficient activation of the mGlu 2/3 receptor in the brain.…”

“…The CSF-to-plasma exposure ratios of MGS0008 were calculated to be 3.66% (C max ) and 4.94% (AUC), respectively, which is higher than the CSF-to-plasma AUC ratio observed in rats (2.8%). 26 In the SAD and MAD studies, the urinary excretion rate of MGS0008 ranged from 29.38 to 69.01% of the administered doses across the dose range of 5-80 mg (Table 5), while the urinary excretion rate of MGS0274 was around 1% of the administered doses (data not shown). The renal clearance of MGS0008 ranged from 4.238-6.180 L h −1 , which was approximately equal to or less than the human glomerular filtration rate (5.88-7.86 L h −1 ), 28 suggesting that renal MGS0008 elimination is less likely to be by tubular secretion or reabsorption in humans.…”

“…24,25 Recently, we synthesized an ester- that the prodrug was rapidly converted into MGS0008 in monkeys after oral administration, and that 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. 26 Moreover, MGS0008 was detected in the cerebrospinal fluid (CSF) in rats after oral administration of MGS0008. 26 Collectively, MGS0274 besylate is an appropriate tool to be used for the proof-of-concept study in human subjects.…”

“…26 Moreover, MGS0008 was detected in the cerebrospinal fluid (CSF) in rats after oral administration of MGS0008. 26 Collectively, MGS0274 besylate is an appropriate tool to be used for the proof-of-concept study in human subjects. Here we report safety, tolerability and pharmacokinetics (PK) of single and multiple doses of TS-134, of which MGS0274 besylate is the active ingredient, in healthy subjects, as well as preclinical data, to show pharmacological profiles of MGS0008.…”

“…(1S,2S,3S,5R,6S)‐2‐amino‐3‐fluorobicyclo[3.1.0]hexane‐2,6‐dicarboxylic acid (MGS0008) is a potent and selective orthosteric mGlu 2/3 receptor agonist which has been demonstrated to exert antipsychotic‐like effects in animal models 24,25 . Recently, we synthesized an ester‐based lipophilic prodrug of MGS0008, (1S,2S,3S,5R,6S)‐2‐amino‐3‐ fluoro‐6‐({(1S)‐1‐[({[(1R,2S,5R)‐5‐methyl‐2‐(propan‐2‐yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane‐2‐carboxylic acid monobenzenesulfonate (MGS0274 besylate), and demonstrated that the prodrug was rapidly converted into MGS0008 in monkeys after oral administration, and that 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 26 . Moreover, MGS0008 was detected in the cerebrospinal fluid (CSF) in rats after oral administration of MGS0008 26 .…”