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

Abstract：

: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).

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Urabe H,Miyakoshi N,Ohtake N,Nozoe A,Ochi M,Fukasawa M,Kinoshita K,Yamaguchi JI,Marumo T,Hikichi H,Chaki S,Hashihayata T

doi

10.1016/j.ejmech.2020.112521

subject

Has Abstract

pub_date

2020-10-01 00:00:00

pages

112521

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(20)30493-1

journal_volume

203

pub_type

杂志文章

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