Efficient, large-scale synthesis and preclinical studies of MRS5698, a highly selective A3 adenosine receptor agonist that protects against chronic neuropathic pain

摘要: We reported that 2-(3,4-difluorophenylethynyl)-N (6)-3-chlorobenzyl (N)-methanocarba adenosine derivative 1 (MRS5698) binds selectively to human and mouse A3 receptors (A3ARs, K i 3 nM). It is becoming an important pharmacological tool for defining A3AR effects orally active in a chronic neuropathic pain model. Here, we introduce new synthetic route MRS5698 from D-ribose, suitable scale-up on multi-gram scale, measure vitro vivo ADME-Tox parameters. was very stable vitro, failed inhibit CYPs at <10 μM, largely bound plasma proteins. well tolerated the rat doses of ≤200 mg/kg i.p. A dose displayed t 1/2 1.09 h Cmax 204 nM with AUC 213 ng × h/mL. CACO-2 bidirectional transport studies suggested intestinal efflux (efflux ratio 86). Although oral %F only 5 %, beneficial effect reverse lasted least 2 CCI model rats, using same vehicle administration high dose. The stability, low toxicity, lack CYP interaction, pharmacokinetic half-life, efficacy suggest preferred compound further consideration as treatment pain.