title: Quinazolines as adenosine receptor antagonists: SAR and selectivity for A2B receptors.
abstract: We have recently reported the discovery of numerous new compounds that are selective inhibitors of all of the subtypes of the adenosine receptor family via a pharmacophore database searching and screening strategy. During the course of this work we made the unexpected discovery of a potent A(2B) receptor antagonist, 4-methyl-7-methoxyquinazolyl-2-(2'-amino-4'-imidazolinone) (38, CMB 6446), which showed selectivity for this receptor and functioned as an antagonist, with a binding K(i) value of 112 nM. We explored the effects of both substituent- and ring-structural variations on the receptor affinity in this series of derivatives, which were found to be mostly non-selective adenosine receptor ligands with K(i) values in the micromolar range. Since no enhancement of A(2B) receptor affinity of 38 was achieved, the previously reported pharmacophore-based searching strategy yielded the most potent and selective structurally-related hit in the database originally searched.
authors.affiliation: ChemBridge Corporation, 16981 Via Tazon, Suite G, San Diego, CA 92127, USA.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Webb
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Lvovskiy
authors.forename: Soon Ai
authors.initials: SA
authors.lastname: Kim
authors.forename: Xiao duo
authors.initials: Xd
authors.lastname: Ji
authors.forename: Neli
authors.initials: N
authors.lastname: Melman
authors.forename: Joel
authors.initials: J
authors.lastname: Linden
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D016208:Databases, Factual; D006801:Humans; D058915:Purinergic P1 Receptor Antagonists; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D043704:Receptor, Adenosine A2B; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014316:Tritium
chemical_list: D058915:Purinergic P1 Receptor Antagonists; D011799:Quinazolines; D043704:Receptor, Adenosine A2B; D014316:Tritium