Potent and orally bioavailable 8-bicyclo[2.2.2]octylxanthines as adenosine A1 receptor antagonists.
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.
Kiesman
William F
WF
Department of Chemistry, Biogen Idec, Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, USA. william.kiesman@biogenidec.com
Zhao
Jin
J
Conlon
Patrick R
PR
Dowling
James E
JE
Petter
Russell C
RC
Lutterodt
Frank
F
Jin
Xiaowei
X
Smits
Glenn
G
Fure
Mary
M
Jayaraj
Andrew
A
Kim
John
J
Sullivan
Gail
G
Linden
Joel
J
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
D058916:Adenosine A1 Receptor Antagonists; C505954:BG 9928; D014970:Xanthines