title: 2,6,8-trisubstituted 1-deazapurines as adenosine receptor antagonists.
abstract: In this study we developed a refined pharmacophore model for antagonists of the human adenosine A1 receptor, based on features of known pyrimidine and purine derivatives. The adoption of these updated criteria assisted us in synthesizing a series of 1-deazapurines with consistently high affinity as inverse agonists for the adenosine A1 receptor. These 1-deazapurines (otherwise known as 3H-imidazo[4,5-b]pyridines) were substituted at their 2- and 6-positions, yielding a series with five of the derivatives displaying Ki values in the subnanomolar range. The most potent of these, compound 10 (LUF 5978), displayed an affinity of 0.55 nM at the human adenosine A1 receptor with >300-fold and 45-fold selectivity toward A2A and A3 receptors, respectively. Compound 14 (LUF 5981, Ki = 0.90 nM) appeared to have the best overall selectivity with respect to adenosine A2A (>200-fold) and A3 (700-fold) receptors.
authors.affiliation: Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Post Office Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: Lisa C W
authors.initials: LC
authors.lastname: Chang
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: Joost
authors.initials: J
authors.lastname: Westerhout
authors.forename: Thomas
authors.initials: T
authors.lastname: Spangenberg
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; D058917:Adenosine A2 Receptor Antagonists; D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D013329:Structure-Activity Relationship
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D058918:Adenosine A3 Receptor Antagonists; D007093:Imidazoles; D011725:Pyridines