Chemistry:Indolidan
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]
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
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]
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
- Adibendan also uses 3,3-dimethyloxindole starting material.
References
- ↑ 1.0 1.1 "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. October 1986. doi:10.1021/jm00160a006. PMID 3761304.
- ↑ "Pharmacology of LY195115, a potent, orally active cardiotonic with a long duration of action". Journal of Cardiovascular Pharmacology 9 (4): 425–434. April 1987. doi:10.1097/00005344-198704000-00007. PMID 2438505.
- ↑ "LY195115: a potent, selective inhibitor of cyclic nucleotide phosphodiesterase located in the sarcoplasmic reticulum.". Molecular Pharmacology 30 (6): 609–616. December 1986. doi:10.1016/S0026-895X(25)10404-5. ISSN 0026-895X. PMID 2946929.
- ↑ "Phosphodiesterase III inhibitors for heart failure". The Cochrane Database of Systematic Reviews 2005 (1). January 2005. doi:10.1002/14651858.CD002230.pub2. PMID 15674893.
- ↑ "A Review on Pyridazinone Ring Containing Various Cardioactive Agents". Journal of Chemical Reviews 1 (1): 66–77. 10 January 2019. doi:10.33945/sami/jcr.2019.1.6677.
- ↑ "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. 12 August 2016. doi:10.4314/tjpr.v15i7.30.
- ↑ The organic chemistry of drug synthesis. 5. Wiley. 1995. ISBN 978-0-471-58959-4.
- ↑ Robertson DW, "Cardiotonic agents", US patent 4647564, issued 3 March 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. April 1987. doi:10.1021/jm00387a007. PMID 3031290.
- ↑ 10.0 10.1 "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. April 1986. doi:10.1002/jlcr.2580230402.
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