Discovery and SAR of novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5). Issue 6 (15th March 2015)

• Record Type: Journal Article
• Authors: Martín-Martín, María Luz; Bartolomé-Nebreda, José Manuel; Conde-Ceide, Susana; Alonso de Diego, Sergio A.; López, Silvia; Martínez-Viturro, Carlos M.; Tong, Han Min; Lavreysen, Hilde; Macdonald, Gregor J.; Steckler, Thomas; Mackie, Claire; Bridges, Thomas M.; Daniels, J. Scott; Niswender, Colleen M.; Noetzel, Meredith J.; Jones, Carrie K.; Conn, P. Jeffrey; Lindsley, Craig W.; Stauffer, Shaun R.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 6(2015)
• Page Start: 1310
• Page End: 1317
• Publication Date: 2015-03-15
• Subjects: Positive allosteric modulator (PAM) -- Metabotropic glutamate receptor 5 (mGlu5) -- Imidazopyrimidinone -- Dihydroimidazopyrimidinone -- Schizophrenia; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.01.038
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: We report the discovery and SAR of two novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as metabotropic glutamate receptor 5 (mGlu5 ) positive allosteric modulators (PAMs). Exploration of several structural features in the western and eastern part of the imidazopyrimidinone core and combinations thereof, revealed compound4a as a mGlu5 PAM with good in vitro potency and efficacy, acceptable drug metabolism and pharmacokinetic (DMPK) properties and in vivo efficacy in an amphetamine-based model of psychosis. However, the presence of CNS-mediated adverse effects in preclinical species precluded any further in vivo evaluation.