Discovery of MGS0274, an ester prodrug of a metabotropic glutamate receptor 2/3 agonist with improved oral bioavailability

• Published in: European journal of medicinal chemistry Vol. 203; pp. 112521 - 112532
• Main Authors: Urabe, Hiroki, Miyakoshi, Naoki, Ohtake, Norikazu, Nozoe, Akiko, Ochi, Motoki, Fukasawa, Misako, Kinoshita, Kohnosuke, Yamaguchi, Jun-ichi, Marumo, Toshiyuki, Hikichi, Hirohiko, Chaki, Shigeyuki, Hashihayata, Takashi
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.10.2020; Elsevier
• Subjects: Administration, Oral; Animals; Biological Availability; Chemistry, Medicinal; Drug Design; Esters - chemistry; Esters - metabolism; Esters - pharmacokinetics; Esters - pharmacology; Haplorhini; Improved oral bioavailability; Life Sciences & Biomedicine; mGlu2/3 receptor agonist; MGS0008; MGS0274; Pharmacology & Pharmacy; Prodrug; Prodrugs - metabolism; Receptors, Metabotropic Glutamate - agonists; Science & Technology; Stereoisomerism; TS-134; MGS0008; mGlu; mGlu2/3 receptor agonist; MGS0274; TS-134; Prodrug; DMF; iv; Improved oral bioavailability; po; BA; DRUG; VITRO; DESIGN; ACID; CYNOMOLGUS MONKEY; DOG
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112521

We previously reported that MGS0008 is a selective group II metabotropic glutamate receptor (mGlu2/3 receptor) agonist that is effective in animal models of schizophrenia. MGS0008 is a highly hydrophilic glutamate analog and is therefore expected to show low oral bioavailability in humans. To improve the oral bioavailability of MGS0008, ester prodrugs of MGS0008 were synthesized and their usefulness was evaluated. Among the prodrugs, the l-menthol-ester prodrug 4h demonstrated preferable lipophilicity, good chemical stability, and a high conversion rate to MGS0008 in human and monkey liver microsomes. A pharmacokinetic study in monkeys revealed that the oral bioavailability of MGS0008 after oral dosing of compound 4h was approximately 15-fold higher than that after oral dosing of MGS0008. Based on these findings, a diastereomer of compound 4h (compound 4j, or MGS0274), was selected as a candidate for clinical drug development, and its besylate is currently under development for the treatment of schizophrenia (Development code: TS-134). [Display omitted] •MGS0008, an mGlu2/3 receptor agonist, was expected to show low oral bioavailability (BA) in humans.•The prodrug 4h exhibited a 15-fold improvement in oral BA compared to MGS0008 in a monkey pharmacokinetic study.•The prodrug was scarcely detected in the plasma.•The besylate salt of compound 4j (MGS0274), a diastereomer of 4h, is under development for the treatment of schizophrenia.