title: Potent and orally bioavailable 8-bicyclo[2.2.2]octylxanthines as adenosine A1 receptor antagonists.
abstract: In the search for a selective adenosine A1 receptor antagonist with greater aqueous solubility than the compounds currently in clinical trials as diuretics, a series of 1,4-substituted 8-cyclohexyl and 8-bicyclo[2.2.2]octylxanthines were investigated. The binding affinities of a variety of cyclohexyl and bicyclo[2.2.2]octylxanthines for the rat and human adenosine A1, A2A, A2B, and A3 receptors are presented. Bicyclo[2.2.2]octylxanthine 16 exhibited good pharmaceutical properties and in vivo activity in a rat diuresis model (ED50=0.3 mg/kg po). Optimization of the bridgehead substituent led to propionic acid 29 (BG9928), which retained high potency (hA1, Ki=7 nM) and selectivity for the adenosine A1 receptor (915-fold versus adenosine A2A receptor; 12-fold versus adenosine A2B receptor) with improved oral efficacy in the rat diuresis model (ED50=0.01 mg/kg) as well as high oral bioavailability in rat, dog, and cynomolgus monkey.
authors.affiliation: Department of Chemistry, Biogen Idec, Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, USA. william.kiesman@biogenidec.com
authors.forename: William F
authors.initials: WF
authors.lastname: Kiesman
authors.forename: Jin
authors.initials: J
authors.lastname: Zhao
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Conlon
authors.forename: James E
authors.initials: JE
authors.lastname: Dowling
authors.forename: Russell C
authors.initials: RC
authors.lastname: Petter
authors.forename: Frank
authors.initials: F
authors.lastname: Lutterodt
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Jin
authors.forename: Glenn
authors.initials: G
authors.lastname: Smits
authors.forename: Mary
authors.initials: M
authors.lastname: Fure
authors.forename: Andrew
authors.initials: A
authors.lastname: Jayaraj
authors.forename: John
authors.initials: J
authors.lastname: Kim
authors.forename: Gail
authors.initials: G
authors.lastname: Sullivan
authors.forename: Joel
authors.initials: J
authors.lastname: Linden
mesh_terms: D058916:Adenosine A1 Receptor Antagonists; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004231:Diuresis / Q000187:drug effects; D004285:Dogs; D006325:Heart Atria / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D058916:Adenosine A1 Receptor Antagonists; C505954:BG 9928; D014970:Xanthines