- 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
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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.
- Hao, Junliang,Dehlinger, Veronique,Fivush, Adam M.,Rudyk, Helene C.E.,Britton, Thomas C.,Hollinshead, Sean P.,Vokits, Benjamin P.,Clark, Barry P.,Henry, Steven S.,Massey, Steven M.,Peng, Langu,Dressman, Bruce A.,Heinz, Beverly A.,Roberts, Edda F.,Bracey-Walker, Mallorie R.,Swanson, Steven,Catlow, John T.,Love, Patrick L.,Tepool, Anita D.,Peters, Steven C.,Simmons, Rosa Maria A.,Iyengar, Smriti,McKinzie, David L.,Monn, James A.
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- 3-INDAZOLYL-4-PYRIDYLISOTHIAZOLES
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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.
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(2009/10/18)
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