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.
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.
Forest
M C
MC
SmithKline Beecham Laboratoires Pharmaceutiques, Unité de Recherche, Saint Grégoire, France.
Lahouratate
P
P
Martin
M
M
Nadler
G
G
Quiniou
M J
MJ
Zimmermann
R G
RG
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D002316:Cardiotonic Agents; D007211:Indoles; D010726:Phosphodiesterase Inhibitors; D013829:Thiadiazines; C072326:5-(3,6-dihydro-2-oxo-2H-1,3,4-thiadiazin-5-yl)-1,3-dihydro-3- methyl-3-methylthio-2H-indol-2-one; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D002118:Calcium