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

Abstract

The safety and pharmacokinetics of single and multiple doses of a novel mGlu 2/3 receptor agonist prodrug, MGS0274 besylate (TS-134), were investigated in healthy subjects. Methods: Phase 1 single-ascending dose (5-20 mg) and multiple-ascending dose titration (5-80 mg) studies were conducted in healthy male and female subjects. Both studies were randomized, double-blinded and placebo-controlled. In one cohort of single-ascending dose study (10 mg), concentrations of MGS0008, the active compound, in the cerebrospinal fluid (CSF) were measured for up to 24 hours postdose. Results: Following single and multiple oral administrations, MGS0274 was rapidly absorbed and extensively converted into MGS0008, which reached a maximum concentration (C max) in plasma within 4 hours postdose and declined with a terminal half-life (t 1/2) of around 10 hours. Plasma exposure to MGS0274 was minimal, accounting for approximately 3% of the area under the concentration-time curve (AUC) of MGS0008. Plasma C max and AUC of MGS0008 at steady state increased dose proportionally (5-80 mg). MGS0008 penetrated into CSF, with a CSF-to-plasma C max ratio of 3.66%, and was eliminated with a t 1/2 of approximately 16 hours. The most frequent treatment-emergent adverse events observed following single and multiple oral administration included headache, nausea, somnolence, dizziness and vomiting. Conclusion: TS-134 is orally bioavailable in humans and converts rapidly and extensively to MGS0008, which exhibits good CSF penetration. Orally administered TS-134 was safe and generally well-tolerated; hence, TS-134 is a promising candidate for further clinical development for the treatment of disorders in which glutamatergic abnormalities are involved, such as schizophrenia.

Prodrugs as empowering tools in drug discovery and development: recent strategic applications of drug delivery solutions to mitigate challenges associated with lead compounds and drug candidates

“…The parent released from 2cs exhibited good brain penetration as was evident from the cerebrospinal fluid (CSF) exposure (CSF/plasma C max ratio = 3.7). 142 Although the permeability-enhancing prodrug approach by masking the polar group has been explored for 2cp , a completely different PepT1-mediated transporter approach has been reported to 2co belonging to the same class (see Section 2.4).…”

Metabotropic Glutamate Receptors As Emerging Targets for the Treatment of Schizophrenia

“…Group II (mGlu 2/3 ) receptor agonists show efficacy for treating behavioral correlates of schizophrenia Agonists of mGlu 2/3 receptors can reverse the behavioral effects of NMDA receptor antagonists, including induction of hyperlocomotion, stereotypy, and heightened anxiety in rodents (Moghaddam and Adams, 1998;Rorick-Kehn et al, 2007;Watanabe et al, 2020). Further, the mGlu 2/3 receptor agonist, LY354740, reduced PCP-induced working memory deficits in mice (Moghaddam and Adams, 1998) and improved working memory impairments induced by ketamine infusion in healthy human subjects (Krystal et al, 2005).…”

“…Further, it will be important to tease apart the relative contributions of mGlu 2 and mGlu 3 receptors in mediating beneficial effects of mGlu 2/3 receptor agonists.Recently, LY2140023 was tested in phase Ib proof of concept studies where high dose of LY2140023 (320 mg/d for 10 days) significantly reduced ketamine-induced Brief Psychiatric Rating Scale (BPRS) total symptoms(Kantrowitz et al, 2020). However, it did not significantly inhibit ketamine-induced changes in the pharmacoBOLD in the dorsal anterior cingulate cortex (dACC) suggesting that the tested dose might still be low for optimal target engagement.Besides LY2140023, a novel mGlu 2/3 receptor agonist prodrug, TS-134 (MGS0274 besylate) entered the clinical trials and found to be safe and well-tolerated in double-blinded and placebo-controlled dose response phase -1 clinical trial conducted in healthy subjects(Watanabe et al, 2020). Further clinical studies reported reductions in both ketamine-induced BPRS positive symptoms and pharmacoBOLD in the dACC, left caudate and NAc after treatment with low-dose of TS-134 (20 mg/d for 6 days)(Kantrowitz et al, 2020).…”

Regulation of Glutamatergic Activity via Bidirectional Activation of Two Select Receptors as a Novel Approach in Antipsychotic Drug Discovery

“…An ester-based lipophilic prodrug of another mGlu 2/3 agonist, MGS0008, was designed to avoid undesirable adverse effects [ 123 ]. MGS0274 besylate exhibited a 15-fold improvement in oral bioavailability compared to MGS0008, and its administration to patients was accompanied by fewer toxic effects caused by its unnecessary exposure [ 120 , 123 , 124 ].…”