title: Discovery of 7-oxopyrazolo[1,5-a]pyrimidine-6-carboxamides as potent and selective CB(2) cannabinoid receptor inverse agonists.
abstract: We recently described the medicinal chemistry of a new series of heteroaryl-4-oxopyridine/7-oxopyrimidines as CB2 receptor partial agonists, showing that the functionality of these ligands is controlled by the nature of the heteroaryl function condensed with the pyridine ring. We describe herein the design and synthesis of the 7-oxopyrazolo[1,5-a]pyrimidine-6-carboxamides, structural isomers of our previously reported pyrazolo[3,4-b]pyridines. All of the new compounds showed high affinity and selectivity for the CB2 receptor in the nanomolar range. In 3,5-cyclic adenosine monophosphate (cAMP) assays, the novel series shows stimulatory effects on forskolin-induced cAMP production acting as inverse agonists.
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy. tbj@unife.it
authors.forename: Mojgan
authors.initials: M
authors.lastname: Aghazadeh Tabrizi
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.forename: Giulia
authors.initials: G
authors.lastname: Saponaro
authors.forename: Allan R
authors.initials: AR
authors.lastname: Moorman
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.forename: Delia
authors.initials: D
authors.lastname: Preti
authors.forename: Stefania
authors.initials: S
authors.lastname: Baraldi
authors.forename: Emanuela
authors.initials: E
authors.lastname: Ruggiero
authors.forename: Cristina
authors.initials: C
authors.lastname: Tintori
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vincenzi
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D054314:Drug Inverse Agonism; D006801:Humans; D008297:Male; D008958:Models, Molecular; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D011720:Pyrazoles; D011743:Pyrimidines; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000242:Cyclic AMP