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

Satoru Ito; Atsushi Satoh; Yasushi Nagatomi; Yukari Hirata; Gentaroh Suzuki; Toshifumi Kimura; Akio Satow; Shunsuke Maehara; Hirohiko Hikichi; Mikiko Hata; Hiroshi Kawamoto; Hisashi Ohta

doi:10.1016/j.bmc.2008.09.060

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

Bioorg Med Chem. 2008 Nov 15;16(22):9817-29. doi: 10.1016/j.bmc.2008.09.060. Epub 2008 Sep 30.

Authors

Satoru Ito¹, Atsushi Satoh, Yasushi Nagatomi, Yukari Hirata, Gentaroh Suzuki, Toshifumi Kimura, Akio Satow, Shunsuke Maehara, Hirohiko Hikichi, Mikiko Hata, Hiroshi Kawamoto, Hisashi Ohta

Affiliation

¹ Tsukuba Research Institute, Banyu Pharmaceutical CO., LTD, 3 Okubo, Tsukuba 300-2611, Japan. satoru_ito@merck.com

PMID: 18849168
DOI: 10.1016/j.bmc.2008.09.060

Abstract

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 10-30mg/kg in an animal model.

MeSH terms

Administration, Oral
Animals
CHO Cells
Cricetinae
Cricetulus
Humans
Inhibitory Concentration 50
Mice
Microsomes, Liver / metabolism
Pyridines / chemical synthesis
Pyridines / chemistry*
Pyridines / pharmacology*
Rats
Receptors, Metabotropic Glutamate / antagonists & inhibitors*
Receptors, Metabotropic Glutamate / metabolism
Structure-Activity Relationship

Substances

Pyridines
Receptors, Metabotropic Glutamate
metabotropic glutamate receptor type 1