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

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 16; pp. 4493 - 4500
• Main Authors: Kubas, Holger, Meyer, Udo, Krueger, Bjoern, Hechenberger, Mirko, Vanejevs, Maksims, Zemribo, Ronalds, Kauss, Valerjans, Ambartsumova, Raisa, Pyatkin, Ilya, Polosukhin, Alexey I., Abel, Ulrich
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.08.2013; Elsevier
• Subjects: Allosteric modulator; Allosteric properties; Allosteric Regulation - drug effects; Animals; Cells, Cultured; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Drug Discovery; Drug Evaluation, Preclinical; drugs; dyskinesia; glutamic acid; Humans; Inhibitory Concentration 50; L-dopa; l-DOPA induced dyskinesia; Life Sciences & Biomedicine; Metabotropic glutamate receptor; mGluR5; Models, Molecular; Pharmacology & Pharmacy; Physical Sciences; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacology; Quinazolinones - chemistry; Quinazolinones - pharmacology; Rats; Receptor, Metabotropic Glutamate 5 - agonists; Receptors, Metabotropic Glutamate - agonists; Science & Technology; screening; Structure-Activity Relationship; structure-activity relationships; Toluidines - chemistry; Toluidines - pharmacology; User-Computer Interface; Virtual screening; Virtual screening; Allosteric modulator; l-DOPA induced dyskinesia; mGluR5; Metabotropic glutamate receptor; ACTIVATION; ANTAGONIST; SERIES; ADX10059; MGLU; SYMPTOMS; POTENT; L-DOPA induced dyskinesia; GASTROESOPHAGEAL-REFLUX DISEASE; AGENTS; INHIBITORS
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.06.049

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.