Discovery of MGS0274, an ester prodrug of a metabotropic glutamate receptor 2/3 agonist with improved oral bioavailability
| Autor: | Naoki Miyakoshi, Motoki Ochi, Toshiyuki Marumo, Misako Fukasawa, Takashi Hashihayata, Hiroki Urabe, Akiko Nozoe, Junichi Yamaguchi, Kohnosuke Kinoshita, Shigeyuki Chaki, Norikazu Ohtake, Hirohiko Hikichi |
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| Rok vydání: | 2020 |
| Předmět: |
Agonist
medicine.drug_class Administration Oral Biological Availability Pharmacology Receptors Metabotropic Glutamate 01 natural sciences 03 medical and health sciences Pharmacokinetics Drug Discovery medicine Animals Prodrugs 030304 developmental biology 0303 health sciences 010405 organic chemistry Chemistry Organic Chemistry Glutamate receptor Esters Stereoisomerism General Medicine Haplorhini Prodrug 0104 chemical sciences Bioavailability Metabotropic glutamate receptor Drug Design Lipophilicity Metabotropic glutamate receptor 2 |
| Zdroj: | European journal of medicinal chemistry. 203 |
| ISSN: | 1768-3254 |
| Popis: | 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). |
| Databáze: | OpenAIRE |
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