Potent and orally bioavailable 8-bicyclo[2.2.2]octylxanthines as adenosine A1 receptor antagonists |
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Authors: | Kiesman William F Zhao Jin Conlon Patrick R Dowling James E Petter Russell C Lutterodt Frank Jin Xiaowei Smits Glenn Fure Mary Jayaraj Andrew Kim John Sullivan Gail Linden Joel |
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Institution: | Department of Chemistry, Biogen Idec, Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, USA. william.kiesman@biogenidec.com |
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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-bicyclo2.2.2]octylxanthines were investigated. The binding affinities of a variety of cyclohexyl and bicyclo2.2.2]octylxanthines for the rat and human adenosine A1, A2A, A2B, and A3 receptors are presented. Bicyclo2.2.2]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. |
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