4.5 Article

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

Journal

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 26, Issue 8, Pages 1894-1900

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2016.03.026

Keywords

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)

Funding

  1. NIMH [U19 MH097056]
  2. NIDA [R01 DA023947]
  3. Vanderbilt Institute of Chemical Biology [VICB 1-04-209-9012]

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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.

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