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. Issue 8 (15th April 2016)

• Record Type: Journal Article
• Authors: Felts, Andrew S.; Rodriguez, Alice L.; Morrison, Ryan D.; Venable, Daryl F.; Blobaum, Anna L.; Byers, Frank W.; Daniels, J. Scott; Niswender, Colleen M.; Jones, Carrie K.; Conn, P. Jeffrey; Lindsley, Craig W.; Emmitte, Kyle A.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 8(2016)
• Page Start: 1894
• Page End: 1900
• Publication Date: 2016-04-15
• Subjects: Metabotropic glutamate receptor subtype 1 (mGlu1) -- Metabotropic glutamate receptor subtype 5 (mGlu5) -- Negative allosteric modulator (NAM) -- Central nervous system (CNS) -- G-protein coupled receptor (GPCR); Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.03.026
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Selective negative allosteric modulators (NAMs) of each of the group I metabotropic glutamate receptors (mGlu1 and mGlu5 ) 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 mGlu1/5 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.