Design, Synthesis, and Structure–Activity Relationships of 3,4-Dihydropyridopyrimidin-2(1H)-one Derivatives as a Novel Class of Sodium/Calcium Exchanger Inhibitor

Abstract

Design, synthesis, and structure–activity relationships for 3,4-dihydropyridopyrimidin-2(1H)-one derivatives, which are aza-3,4-dihydro-2(1H)-quinazolinone derivatives, as the sodium/calcium (Na⁺/Ca²⁺) exchanger inhibitors are discussed. These studies based on 3,4-dihydro-2(1H)-quinazolinone derivatives led to the discovery of a structurally novel and potent Na⁺/Ca²⁺ exchanger inhibitor, 3,4-dihydropyridopyrimidin-2(1H)-one derivative (26), with an IC₃₀ value of 0.02 μM. Compound 26 directly inhibited the Na⁺-dependent Ca²⁺ influx via the Na⁺/Ca²⁺ exchanger after Na⁺-free treatment in cardiomyocytes.