title: Efficient, large-scale synthesis and preclinical studies of MRS5698, a highly selective A3 adenosine receptor agonist that protects against chronic neuropathic pain.
abstract: We reported that 2-(3,4-difluorophenylethynyl)-N (6)-3-chlorobenzyl (N)-methanocarba adenosine derivative 1 (MRS5698) binds selectively to human and mouse A3 adenosine receptors (A3ARs, K i 3 nM). It is becoming an important pharmacological tool for defining A3AR effects and is orally active in a chronic neuropathic pain model. Here, we introduce a new synthetic route for MRS5698 from D-ribose, suitable for a scale-up on a multi-gram scale, and we measure in vitro and in vivo ADME-Tox parameters. MRS5698 was very stable in vitro, failed to inhibit CYPs at <10 μM, and was largely bound to plasma proteins. It was well tolerated in the rat at doses of ≤200 mg/kg i.p. A 1 mg/kg i.p. dose in the mouse displayed t 1/2 of 1.09 h and plasma Cmax of 204 nM at 1 h with an AUC of 213 ng × h/mL. CACO-2 bidirectional transport studies suggested intestinal efflux of MRS5698 (efflux ratio 86). Although the oral %F is only 5 %, the beneficial effect to reverse pain lasted for at least 2 h in the CCI model in rats, using the same vehicle for oral administration of a high dose. The stability, low toxicity, lack of CYP interaction, pharmacokinetic half-life, and in vivo efficacy suggest that MRS5698 is a preferred compound for further consideration as a treatment for neuropathic pain.
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Dilip K
authors.initials: DK
authors.lastname: Tosh
authors.forename: Janak
authors.initials: J
authors.lastname: Padia
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvemini
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D058909:Adenosine A3 Receptor Agonists / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D000818:Animals; D001693:Biological Transport, Active; D001798:Blood Proteins / Q000378:metabolism; D018938:Caco-2 Cells; D002908:Chronic Disease; D003251:Constriction, Pathologic / Q000150:complications; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver; D009152:Mutagenicity Tests; D009437:Neuralgia / Q000188:drug therapy*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D058909:Adenosine A3 Receptor Agonists; D001798:Blood Proteins; C000607789:MRS5698; D000241:Adenosine