Development of Novel, CNS Penetrant Positive Allosteric Modulators for the Metabotropic Glutamate Receptor Subtype 1 (mGlu(1)), Based on an N-(3-Chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxam ide Scaffold, That Potentiate Wild Type and Mutant mGlu(1) Receptors Found in Schizophrenics

作者：Garcia Barrantes Pedro M; Cho Hyekyung P; Niswender Colleen M; Byers Frank W; Locuson Charles W; Blobaum Anna L; Xiang Zixiu; Rook Jerri M; Conn P Jeffrey; Lindsley Craig W^*

来源：Journal of Medicinal Chemistry, 2015, 58(20): 7959-7971.

DOI：10.1021/acs.jmedchem.5b00727

The therapeutic potential of selective mGlu(1) activation is vastly unexplored relative to the other group I mGlu receptor, mGlu(5); therefore, our lab has focused considerable effort toward developing mGlu(1) positive allosteric modulators (PAMs) suitable as in vivo proof of concept tool compounds. Optimization of a series of mGlu(1) PAMs based on an N-(3-chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide scaffold provided 17e, a potent (mGlu(1) EC50 = 31.8 nM) and highly CNS penetrant (brain to plasma ratio (K-p) of 1.02) mGlu(1) PAM tool compound, that potentiated not only wild-type human mGlu(1) but also mutant mGlu(1) receptors derived from deleterious GRM1 mutations found in schizophrenic patients. Moreover, both electrophysiological and in vivo studies indicate the mGlu(1) ago-PAMs/PAMs do not possess the same epileptiform adverse effect liability as mGlu(5) ago-PAMs/PANIs and maintain temporal activity suggesting a broader therapeutic

• 出版日期2015-10-22