A2B adenosine receptor antagonists: Design, synthesis and biological evaluation of novel xanthine derivatives

Abstract A 2BA doR is a low affinity adenosine receptorthat functions by Gs mediated elevation of cAMP and subsequent downstream signaling. The receptor has been implicated in lung inflammatory disorders like COPD and asthma. Several potent and selective A 2B AdoRantagonists have been reported in literature, however most of the compounds suffer from poor pharmacokinetic profile. Therefore, with the aim to identify novel, potent and selective A 2B AdoRantagonists with improved pharmacokinetic properties, we first explored more constrained form of MRS-1754 ( 4 ). To improve the metabolic stability, several linker modifications were attempted as replacement of amide linker along with different phenyl or other heteroaryls between C8 position of xanthinehead group and terminal phenyl ring. SAR optimization resulted in identification of two novel A 2B AdoRantagonists, 8-{1-[5-Oxo-1-(4-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl]-1H-pyrazol-4-yl}-1,3-dipropyl- xanthine( 31 ) and 8-(1-{2-Oxo-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-1H-pyrazol-4-yl)-1,3-dipropyl- xanthine( 65 ), with high binding affinity (K i = 1 and 1.5 nM, respectively) and selectivity for A 2B AdoRwith very good functional potency of 0.9 nM and 4 nM, respectively. Compound 31 and 65 also displayed good pharmacokinetic properties in mice with 27% and 65% oral bioavailability respectively. When evaluated in in vivo mice model of asthma, compound 65 also inhibited airway inflammation and airway reactivity in ovalbumin induced allergic asthma at 3 mpk dose.