Synthesis and pharmacological properties of novel guanidine derivatives of quinazoline-2,4(1H,3H)-dione

Introduction: Na+/H+ exchanger type 1 (NHE-1) is a validated drug target for the treatment of cardiovascular and ophthalmic diseases due to the cytoprotective, anti-ischemic and anti-inflammatory properties of NHE-1 inhibitors. This article presents data on the synthesis and pharmacological activity studies of novel guanidine derivatives of quinazoline-2,4(1H,3H)-dione 6-11 and reference drugs amiloride, rimeporide, zoniporide, dexamethasone, aminoguanidine, and acetylsalicylic acid. Materials and Methods: Pharmacological properties were assessed using pH-dependent platelets deformation assay, anti-inflammatory activity assay on LPS-stimulated peritoneal macrophages, antiglycation assay, analysis of platelet aggregation in vitro and measurement of intraocular pressure in vivo. Results: Several compounds combine NHE-1 inhibition with antiglaucomic and antiplatelet activity. Compound 11 significantly inhibits pro-inflammatory activation of murine macrophages (IC50 15.64 μM) and effectively suppresses the formation of glycated proteins (38.1±2.6% in C 1 mM). Conclusion: The investigated compounds represent a promising scaffold for development of agents for the treatment of cardiovascular pathologies, glaucoma, excessive inflammation, and late diabetic complications including retina diabetics and thrombosis.