Discovery, synthesis, and structure-activity relationships of 2-aminoquinazoline derivatives as a novel class of metabotropic glutamate receptor 5 negative allosteric modulators

作者：Kubas Holger; Meyer Udo; Krueger Bjoern; Hechenberger Mirko; Vanejevs Maksims; Zemribo Ronalds; Kauss Valerjans; Ambartsumova Raisa; Pyatkin Ilya; Polosukhin Alexey I; Abel Ulrich^*

来源：Bioorganic & Medicinal Chemistry Letters, 2013, 23(16): 4493-4500.

DOI：10.1016/j.bmcl.2013.06.049

• Metabotropic glutamate receptor
• mGluR5
• Allosteric modulator
• Virtual screening
• L-DOPA induced dyskinesia

A virtual screening approach using various in silico methodologies led to the discovery of 2-(m-tolylamino)-7,8-dihydroquinazolin-5(6H)-one (1) as a moderately active negative allosteric modulator (NAM) of the metabotropic glutamate receptor subtype 5 (mGluR5) showing high selectivity against the subtype mGluR1. Modifications of the parent compound by rational design yielded a series of highly potent derivatives which will serve as valuable starting points for further hit-to-lead optimization efforts toward a suitable drug candidate for the treatment of L-DOPA induced dyskinesia.

• 出版日期2013-8-15