Quinazolines as adenosine receptor antagonists: SAR and selectivity for A2B receptors.
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.
Webb
Thomas R
TR
ChemBridge Corporation, 16981 Via Tazon, Suite G, San Diego, CA 92127, USA.
Lvovskiy
Dmitriy
D
Kim
Soon Ai
SA
Ji
Xiao duo
Xd
Melman
Neli
N
Linden
Joel
J
Jacobson
Kenneth A
KA
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
D058915:Purinergic P1 Receptor Antagonists; D011799:Quinazolines; D043704:Receptor, Adenosine A2B; D014316:Tritium