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]

Other namesLY195115

CAS Number

100643-96-7

PubChem CID

5284402

ChemSpider

4447476

Quick facts Clinical data, Other names ...

Indolidan
Clinical data

Other names	LY195115
Identifiers
IUPAC name 3,3-Dimethyl-5-(6-oxo-4,5-dihydro-1H-pyridazin-3-yl)-1H-indol-2-one
CAS Number	100643-96-7
PubChem CID	5284402
ChemSpider	4447476
UNII	0751ZOW7OR
KEGG	D04529
ChEMBL	ChEMBL38224
CompTox Dashboard (EPA)	DTXSID0020739
Chemical and physical data
Formula	C₁₄H₁₅N₃O₂
Molar mass	257.293 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES CC1(C2=C(C=CC(=C2)C3=NNC(=O)CC3)NC1=O)C
InChI 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 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]

References

[1]
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]
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.

Synthesis

See also

References

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