A Novel Class of Cardiotonic Agents: Synthesis and Biological Evaluation of 5-Substituted 3,6-Dihydrothiadiazin-2-ones with Cyclic AMP Phosphodiesterase Inhibiting and Myofibrillar Calcium Sensitizing Properties

Article abstract of DOI:10.1021/jm00079a022

As part of a search for new cardiotonic agents significantly sensitising the myocardial contractile proteins to calcium, together with cardiac cyclic AMP-PDE inhibitory activity, we have discovered that novel 5-substituted 3,6-dihydrothiadiazin-2-ones may fulfill both properties.The sensitising effect of the contractile proteins to calcium, assessed by the shift in the calcium sensitivity of canine cardiac myofibrillar magnesium-dependent ATPase, is determined by steric and electronic requirements.The requirements for phosphodiesterase inhibition, especially that of a near-planar arrangement for the phenyl and thiadiazin-2-one ring are consistent with those already described for analogous pyridazinones.The synthesis and structure-activity relationships are discussed.