5471. Levosimendan

Nomenclature

CAS number: 141505-33-1
[[4-[(4R)-1,4,5,6-Tetrahydro-4-methyl-6-oxo-3-pyridazinyl]phenyl]hydrazono]propanedinitrile; ()-[p[(R)-1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl]phenyl]hydrazone mesoxalonitrile; (R)-simendan; OR-1259; Simdax (Orion).
C14H12N6O; mol wt 280.28.
C 59.99%, H 4.32%, N 29.98%, O 5.71%.

Description and references

Bioactive enantiomer of racemate, simendan. Positive inotropic agent with vasodilating activity. Binds to and sensitizes the myocardial contractile protein, troponin C, to calcium, thereby stabilizing the troponin conformation needed to trigger muscle contraction. Prepn: R. J. Backstrom et al., GB 2251615; P. Nore et al., US 5569657 (1992, 1996 both to Orion). Pharmacology: A. F. E. Rump et al., Pharmacol. Toxicol. 74, 244 (1994). Binding studies: P. Pollesello et al., J. Biol. Chem. 269, 28584 (1994). HPLC determn in plasma: M. Karlsson et al., Biomed. Chromatogr. 11, 54 (1997). Clinical pharmacokinetics: E.-P. Sandell et al., J. Cardiovasc. Pharmacol. 26, Suppl. 1, S57 (1995). Review of mechanism of action: H. Haikala, I.-B. Lindén, ibid. S10-S19 (1995); of pharmacology, toxicology and clinical evaluation: P. S. Pagel et al., Cardiovasc. Drug Rev. 14, 286-316 (1996). Comparison with dobutamine, q.v., in heart failure: F. Follath et al., Lancet 360, 196 (2002).

Chemical structure

Properties

Yellow crystalline powder, mp 210-214°. [α]D25 566° (tetrahydrofurane/methanol). Soluble in water. pKa 6.3. LD50 in male, female mice, male rats (mg/kg): 156, 152, 103 orally; 32, 50, 57 i.v. (Pagel).

Therapeutic Category

Cardiotonic.

Keywords

Cardiotonic