Synthesis and optimization of 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridines as potent and orally-active metabotropic glutamate receptor 5 negative allosteric modulators

• Published in: Bioorganic & medicinal chemistry letters 2017-09, Vol.27 (18), p.4331-4335
• Main Authors: Hirose, Wataru, Kato, Yoshihiro, Natsutani, Itaru, Takata, Makoto, Kitaichi, Maiko, Imai, Satoki, Hayashi, Shun, Arai, Yukiyo, Hoshino, Kohei, Yoshida, Kohzo
• Format: Article
• Language: English
• Subjects: Administration, Oral; Allosteric Regulation - drug effects; Animals; Anti-depressant agent; Antidepressive Agents - administration & dosage; Antidepressive Agents - chemistry; Antidepressive Agents - pharmacology; Behavior, Animal - drug effects; CNS drug discovery; Dose-Response Relationship, Drug; mGluR5; Molecular Structure; Motor Activity - drug effects; Negative allosteric modulator; Pyridines - administration & dosage; Pyridines - chemistry; Pyridines - pharmacology; Rats; Receptor, Metabotropic Glutamate 5 - antagonists & inhibitors; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2017.08.030

[Display omitted] We describe here the design, synthesis and characterization of a series of 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridines as metabotropic glutamate receptor (mGluR) 5 negative allosteric modulators (NAMs). Optimization of the substituents led to the identification of several compounds with good pharmacokinetic profiles, including long half life and high oral bioavailability, in both rats and monkeys. The receptor occupancy test in the rat cortex revealed favorable brain penetration of these compounds. The reprsentative compound 13 produced oral antidepressant-like effect in the rat forced swimming test (MED: 0.3mg/kg, q.d.).