The present invention provides 3-indazoyl-4-pyridylisothiazoles or a pharmaceutically acceptable salt thereof, pharmaceutical compositions thereof, and methods of using the same, as well as processes for preparing the same, and intermediates thereof.
Discovery of (1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide, a potent and orally efficacious mGlu5 receptor negative allosteric modulator
作者:Junliang Hao、Veronique Dehlinger、Adam M. Fivush、Helene C.E. Rudyk、Thomas C. Britton、Sean P. Hollinshead、Benjamin P. Vokits、Barry P. Clark、Steven S. Henry、Steven M. Massey、Langu Peng、Bruce A. Dressman、Beverly A. Heinz、Edda F. Roberts、Mallorie R. Bracey-Walker、Steven Swanson、John T. Catlow、Patrick L. Love、Anita D. Tepool、Steven C. Peters、Rosa Maria A. Simmons、Smriti Iyengar、David L. McKinzie、James A. Monn
DOI:10.1016/j.bmcl.2013.01.009
日期:2013.3
A novel series of selective negative allosteric modulators (NAMs) for metabotropic glutamate receptor 5 (mGlu5) was discovered from an isothiazole scaffold. One compound of this series, (1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide (24), demonstrated satisfactory pharmacokinetic properties and, following oral dosing in rats, produced dose-dependent and long-lasting mGlu5 receptor occupancy. Consistent with the hypothesis that blockade of mGlu5 receptors will produce analgesic effects in mammals, compound 24 produced a dose-dependent reduction in paw licking responses in the formalin model of persistent pain. (c) 2013 Elsevier Ltd. All rights reserved.
Provided herein are compounds of Formula (I), or pharmaceutically acceptable salts thereof, pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of a compound described herein) and methods of synthesizing the same. Also provided herein are methods of treating diseases and/or conditions with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.