N-Alkylpyrido[1′,2′:1,5]pyrazolo-[4,3-d]pyrimidin-4-amines: A new series of negative allosteric modulators of mGlu1/5 with CNS exposure in rodents

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

Felts, Andrew S.^1,2  Rodriguez, Alice L.^1,2  Morrison, Ryan D.^1,2  Venable, Daryl F.^1,2  Blobaum, Anna L.^1,2  Byers, Frank W.^1,2  Daniels, J. Scott^1,2  Niswender, Colleen M.^1,2  Jones, Carrie K.^1,2  Conn, P. Jeffrey^1,2  Lindsley, Craig W.^1,2,3  Emmitte, Kyle A.^1,2,3 

[1] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA

关键词: Metabotropic glutamate receptor subtype 1 (mGlu(1));    Metabotropic glutamate receptor subtype 5 (mGlu(5));    Negative allosteric modulator (NAM);    Central nervous system (CNS);    G-protein coupled receptor (GPCR);   

DOI  :  10.1016/j.bmcl.2016.03.026

来源: Elsevier

【 摘 要 】

Selective negative allosteric modulators (NAMs) of each of the group I metabotropic glutamate receptors (mGlu(1) and mGlu(5)) have been well characterized in the literature and offer potential as therapeutics in several disorders of the central nervous system (CNS). Still, compounds that are potent mGlu(1/5) NAMs with selectivity versus the other six members of the mGlu family as well as the balance of properties required for use in vivo are lacking. A medicinal chemistry effort centered on the identification of a lead series with the potential of delivering such compounds is described in this Letter. Specifically, a new class of pyrido[1',2': 1,5]pyrazolo[4,3-d]pyrimidin-4-amines was designed as a novel isosteric replacement for 4-aminoquinazolines, and compounds from within this chemotype exhibited dual NAM activity at both group I mGlus. One compound, VU0467558 (29), demonstrated near equipotent activity at both receptors, selectivity versus other mGlus, a favorable ancillary pharmacology profile, and CNS exposure in rodents. (C) 2016 Elsevier Ltd. All rights reserved.

【 授权许可】

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