Indolidan

Last updated

Indolidan
Indolidan.svg
Clinical data
Other namesLY195115
Identifiers
  • 3,3-Dimethyl-5-(6-oxo-4,5-dihydro-1H-pyridazin-3-yl)-1H-indol-2-one
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C14H15N3O2
Molar mass 257.293 g·mol−1
3D model (JSmol)
  • CC1(C2=C(C=CC(=C2)C3=NNC(=O)CC3)NC1=O)C
  • InChI=1S/C14H15N3O2/c1-14(2)9-7-8(3-4-11(9)15-13(14)19)10-5-6-12(18)17-16-10/h3-4,7H,5-6H2,1-2H3,(H,15,19)(H,17,18)
  • Key:LZCQFJKUAIWHRW-UHFFFAOYSA-N

Indolidan is a small-molecule cardiotonic agent originally developed by Eli Lilly & Co. for the treatment of heart failure. [1] [2] Structurally classified as a 2-indolinone derivative, it acts primarily as a selective inhibitor of phosphodiesterase 3 (PDE3), thereby enhancing cardiac contractility by increasing intracellular cyclic AMP (cAMP) levels in cardiac myocytes. [3] Indolidan has been investigated in clinical settings for its potential to improve cardiac output in patients with heart failure, but development has not advanced beyond early-phase clinical trials due to concerns about safety and overall efficacy. [4]

Contents

Indolidan belongs to a class or family of chemicals that contain a pyridazinone ring. [5] [6] For example, it is structurally related to Levosimendan, pimobendan, siguazodan, zardaverine.

Synthesis

Indolidan synthesis.svg

A Friedel–Crafts acylation of 3,3-dimethyloxindole [19155-24-9] (4) with succinic anhydride (5) afforded 5-(3,3-dimethyloxindole)-4-oxobutyric acid, PC13620376 (6). Treatment with hydrazine afforded the pyridazinone ring closure, thus completing the synthesis of indolidan (7) proper. [7] [1] [8] [9]

3,3-Dimethyloxindole synthesis.svg

An alternative way to create 3,3-dimethyloxindole (4) starting material is from N'-phenylisobutyrohydrazide [5461-50-7]. Intramolecular ring closure is made to occur upon heating in calcium hydride. [10]

A radiolabelled synthesis with carbon-14 and deuterium has also been described. [10]

See also

References

  1. 1 2 Robertson DW, Krushinski JH, Beedle EE, Wyss V, Pollock GD, Wilson H, et al. (October 1986). "Dihydropyridazinone cardiotonics: the discovery and inotropic activity of 1,3-dihydro-3,3-dimethyl-5-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-2H -indol-2- one". Journal of Medicinal Chemistry. 29 (10): 1832–1840. doi:10.1021/jm00160a006. PMID   3761304.
  2. ↑ Hayes JS, Pollock GD, Wilson H, Bowling N, Robertson DW (April 1987). "Pharmacology of LY195115, a potent, orally active cardiotonic with a long duration of action". Journal of Cardiovascular Pharmacology. 9 (4): 425–434. doi:10.1097/00005344-198704000-00007. PMID   2438505.
  3. ↑ Kauffman RF, Crowe VG, Utterback BG, Robertson DW (December 1986). "LY195115: a potent, selective inhibitor of cyclic nucleotide phosphodiesterase located in the sarcoplasmic reticulum". Molecular Pharmacology. 30 (6): 609–616. doi:10.1016/S0026-895X(25)10404-5. ISSN   0026-895X. PMID   2946929.
  4. ↑ Amsallem E, Kasparian C, Haddour G, Boissel JP, Nony P (January 2005). "Phosphodiesterase III inhibitors for heart failure". The Cochrane Database of Systematic Reviews. 2005 (1) CD002230. doi:10.1002/14651858.CD002230.pub2. PMC   8407097 . PMID   15674893.
  5. ↑ Asif M (10 January 2019). "A Review on Pyridazinone Ring Containing Various Cardioactive Agents". Journal of Chemical Reviews. 1 (1): 66–77. doi: 10.33945/sami/jcr.2019.1.6677 .
  6. ↑ Imran M, Abida A (12 August 2016). "6-(4-Aminophenyl)-4,5-dihydro-3(2H)-pyridazinone - An important chemical moiety for development of cardioactive agents: A review". Tropical Journal of Pharmaceutical Research. 15 (7): 1579. doi: 10.4314/tjpr.v15i7.30 .
  7. ↑ Lednicer D (1995). The organic chemistry of drug synthesis. 5. Wiley. ISBN   978-0-471-58959-4.
  8. ↑ US 4647564,Robertson DW,"Cardiotonic agents",issued 3 March 1987, assigned to Eli Lilly and Co
  9. ↑ Robertson DW, Jones ND, Krushinski JH, Pollock GD, Swartzendruber JK, Hayes JS (April 1987). "Molecular structure of the dihydropyridazinone cardiotonic 1,3-dihydro-3,3-dimethyl-5-(1,4,5,6-tetrahydro-6-oxo-pyridazinyl)- 2H-indol-2-one, a potent inhibitor of cyclic AMP phosphodiesterase". Journal of Medicinal Chemistry. 30 (4): 623–627. doi:10.1021/jm00387a007. PMID   3031290.
  10. 1 2 Robertson DW, Krushinski JH, Kau D (April 1986). "Synthesis of 14 C- and 2 H-labeled 1,3-dihydro-3,3-dimethyl-5-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-2 H -indol-2-one (LY195115), an orally effective positive inotrope". Journal of Labelled Compounds and Radiopharmaceuticals. 23 (4): 343–354. doi:10.1002/jlcr.2580230402.
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