title: 2,4,6-trisubstituted pyrimidines as a new class of selective adenosine A1 receptor antagonists.
abstract: Adenosine receptor antagonists usually possess a bi- or tricyclic heteroaromatic structure at their core with varying substitution patterns to achieve selectivity and/or greater affinity. Taking into account molecular modeling results from a series of potent adenosine A1 receptor antagonists, a pharmacophore was derived from which we show that a monocyclic core can be equally effective. To achieve a compound that may act at the CNS we propose imposing a restriction related to its polar surface area (PSA). In consequence, we have synthesized two novel series of pyrimidines, possessing good potency at the adenosine A1 receptor and desirable PSA values. In particular, compound 30 (LUF 5735) displays excellent A1 affinity (Ki = 4 nM) and selectivity (< or =50% displacement of 1 muM concentrations of the radioligand at the other three adenosine receptors) and has a PSA value of 53 A2.
authors.affiliation: Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: Lisa C W
authors.initials: LC
authors.lastname: Chang
authors.forename: Ronald F
authors.initials: RF
authors.lastname: Spanjersberg
authors.forename: Jacobien K
authors.initials: JK
authors.lastname: von Frijtag Drabbe Künzel
authors.forename: Thea
authors.initials: T
authors.lastname: Mulder-Krieger
authors.forename: Gijs
authors.initials: G
authors.lastname: van den Hout
authors.forename: Margot W
authors.initials: MW
authors.lastname: Beukers
authors.forename: Johannes
authors.initials: J
authors.lastname: Brussee
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: Ijzerman
mesh_terms: D058916:Adenosine A1 Receptor Antagonists; D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D043705:Receptor, Adenosine A2A / Q000187:drug effects; D043684:Receptor, Adenosine A3 / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D008024:Ligands; C495228:N-(4,6-diphenylpyrimidin-2-yl)butyramide; D011743:Pyrimidines; D011744:Pyrimidinones; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3