Discovery and biological profile of 4-(1-aryltriazol-4-yl)-tetrahydropyridines as an orally active new class of metabotropic glutamate receptor 1 antagonist

• Published in: Bioorganic & medicinal chemistry Vol. 16; no. 22; pp. 9817 - 9829
• Main Authors: Ito, Satoru, Satoh, Atsushi, Nagatomi, Yasushi, Hirata, Yukari, Suzuki, Gentaroh, Kimura, Toshifumi, Satow, Akio, Maehara, Shunsuke, Hikichi, Hirohiko, Hata, Mikiko, Kawamoto, Hiroshi, Ohta, Hisashi
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.11.2008; Elsevier
• Subjects: Administration, Oral; Animals; Antagonist; Biological and medical sciences; CHO Cells; Cricetinae; Cricetulus; Glutamatergic system (aspartate and other excitatory aminoacids); Humans; Inhibitory Concentration 50; Medical sciences; mGluRs; Mice; Microsomes, Liver - metabolism; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Oral antagonistic activity; Pharmacology. Drug treatments; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Rats; Receptors, Metabotropic Glutamate - antagonists & inhibitors; Receptors, Metabotropic Glutamate - metabolism; Structure-Activity Relationship; Oral antagonistic activity; Antagonist; mGluRs; Group I mglu glutamate receptor; Stability; Rodentia; Oral administration; mglu1 glutamate receptor; Glutamate receptor; In vitro; Biological activity; Pyridine derivatives; In vivo; Vertebrata; Mammalia; Metabotropic receptor; Mouse; Animal; Triazole derivatives; Water solubility; Ureas; Fluorine Organic compounds; Chemical synthesis; Physicochemical properties
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.09.060

4-(1-Aryltriazol-4-yl)-tetrahydropyridines were designed and synthesized as novel mGluR1 antagonists. We describe here the discovery and the structure–activity relationship (SAR) of a series of 4-(1-Aryltriazol-4-yl)-tetrahydropyridines as novel mGluR1 antagonists. Our extensive chemical modification of lead compound 2 successfully led to fluoropyridine analogs 7j and 1 with improved in vivo antagonistic activities. Among the evaluated compounds, chemically stable urea analog 1 showed oral antagonistic activity at dose ranges of 10–30 mg/kg in an animal model.