A novel series of metabotropic glutamate receptor 5 negative allosteric modulators based on a 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine core
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- 作者：Guillaume Duvey ; Benjamin Perry ; Emmanuel Le Poul ; Sonia Poli ; Beatrice Bonnet ; Nathalie Lambeng ; Delphine Charvin ; Tansy Donovan-Rodrigues ; Hasna¨¤ Haddouk ; Stefania Gagliardi ; Jean-Philippe Rocher
- 关键词：mGlu5 ; Metabotropic ; Pain ; Glutamate ; Allosteric
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2013
- 出版时间：15 August, 2013
- 年：2013
- 卷：23
- 期：16
- 页码：4523-4527
- 全文大小：1261 K
文摘
A series of potent non-acetylinic negative allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5 NAMs) was developed starting from HTS screening hit 1. Potency was improved via iterative SAR, and physicochemical properties were optimized to deliver orally bioavailable compounds acceptable for in vivo testing. A lead molecule from the series demonstrated dose-dependent activity in the second phase of the rat formalin test from 30 mg/kg, and a preliminary PK/PD relationship was established.