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.

Xanthines as Adenosine Receptor Antagonists

“… a h = human; c = cow; d = dog; gp = guinea pig; m= mouse; mk = monkey; r = rat; rb = rabbit; a few data are from functional (cAMP) studies; nd = no data available A 2B b data for the racemate (KFM-19) 1 van Galen et al, 1994 2 Bruns et al, 1986 3 Klotz et al, 1991 4 Bulicz et al, 2006 5 Kim et al, 2002 6 Ukena et al, 1986b 7 Auchampach et al, 1997 8 Klotz et al, 1998 9 Weyler et al, 2006 10 Müller et al, 2000 11 Fozard et al, 2003 12 Auchampach et al, 2009 13 Hayallah et al, 2002 14 Jacobson et al, 1989b 15 Jacobson et al, 1999 16 Schingnitz et al, 1991 17 Müller, 1997 18 Ceccarelli et al, 1995 19 Pfister et al, 1997 20 Kiesman et al, 2006b 21 Kiesman et al, 2006a 22 Massip et al, 2006 23 Doggrell, 2005 24 Noguchi et al, 1997 25 Suzuki et al, 1992a 26 Shimada et al, 1992a …”

Caffeine analogs: biomedical impact

“…A carboxyl moiety in BG 9928 (see Fig. 2) improved water solubility and oral efficacy [32]. Introduction of an ionized sulfonic acid moiety on the 8-phenyl ring resulted in an A 1 -selective antagonist, with only peripheral effects (see DPSPX in Fig.…”

Introduction to Adenosine Receptors as Therapeutic Targets

“…In dogs, both BG9719 and BG9928 have high affinity for both the A 1 AR and A 2B AR (Auchampach et al 2004) with A 2B /A 1 ratios of 21 and 24, respectively (Doggrell 2005). The selectivity of BG 9928 for the human A 1 AR compared to the human A 2B AR is 12 (Kiesman et al 2006). The 8-cyclopentyl derivative DPCPX (8-cyclopentyl-1,3-dipropylxanthine), also known as CPX, which is selective for the A 1 AR in the rat with nanomolar affinity but less selective at the human AR subtypes, has been in clinical trials for cystic fibrosis through a non-AR-related mechanism (Arispe et al 1998).…”