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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Authors: | Junliang Hao Veronique Dehlinger Adam M Fivush Helene CE 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 James A Monn |
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Institution: | 1. Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA;2. Lilly Research Center, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK |
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Abstract: | 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. |
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