Development of Novel, CNS Penetrant Positive Allosteric Modulators for the Metabotropic Glutamate Receptor Subtype 1 (mGlu1), Based on an N-(3-Chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-

详细信息    查看全文

• 作者：Pedro M. Garcia-Barrantes ; Hyekyung P. Cho ; Colleen M. Niswender ; Frank W. Byers ; Charles W. Locuson ; Anna L. Blobaum ; Zixiu Xiang ; Jerri M. Rook ; P. Jeffrey Conn ; Craig W. Lindsley
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：October 22, 2015
• 年：2015
• 卷：58
• 期：20
• 页码：7959-7971
• 全文大小：709K
• ISSN：1520-4804

文摘

The therapeutic potential of selective mGlu₁ activation is vastly unexplored relative to the other group I mGlu receptor, mGlu₅; therefore, our lab has focused considerable effort toward developing mGlu₁ positive allosteric modulators (PAMs) suitable as in vivo proof of concept tool compounds. Optimization of a series of mGlu₁ PAMs based on an N-(3-chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide scaffold provided 17e, a potent (mGlu₁ EC₅₀ = 31.8 nM) and highly CNS penetrant (brain to plasma ratio (K_p) of 1.02) mGlu₁ PAM tool compound, that potentiated not only wild-type human mGlu₁ but also mutant mGlu₁ receptors derived from deleterious GRM1 mutations found in schizophrenic patients. Moreover, both electrophysiological and in vivo studies indicate the mGlu₁ ago-PAMs/PAMs do not possess the same epileptiform adverse effect liability as mGlu₅ ago-PAMs/PAMs and maintain temporal activity suggesting a broader therapeutic window.