Irindalone

Irindalone (INNTooltip International Nonproprietary Name; developmental code name LU-21098 or Lu 21-098) is a predominantly peripherally acting, highly potent, and selective serotonin 5-HT₂ receptor antagonist which was under development for the treatment of hypertension but was never marketed.^[1]^[2]^[3]^[4]^[5]^[6] It is known to act as a serotonin 5-HT_2A and 5-HT_2C receptor antagonist.^[7]^[3]^[8] In addition, unlike ketanserin and cinanserin, the drug blocks the serotonin receptors in the rat fundus strip,^[5] which may correspond to the serotonin 5-HT_2B receptor.^[9]^[10] It shows weak affinity for the α₁-adrenergic receptor, where it is antagonistic as well.^[3]^[5]^[6] Irindalone was first described in the scientific literature by 1988.^[5]^[6] It reached phase 2 clinical trials for hypertension prior to the discontinuation of its development in 1989.^[4]^[2] In addition to hypertension, irindalone was later studied in the early 2000s for use in combination with a selective serotonin reuptake inhibitor (SSRI) to augment serotonin levels via serotonin 5-HT_2C receptor blockade and enhance antidepressant efficacy.^[7]^[8]

Other namesLU-21098; LU21098; Lu 21-098

Drug classSerotonin; 5-HT₂ receptor antagonist; Serotonin 5-HT_2A receptor antagonist

ATC code

None

CAS Number

96478-43-2

Quick facts Clinical data, Other names ...

Irindalone
Clinical data

Other names	LU-21098; LU21098; Lu 21-098
Drug class	Serotonin; 5-HT₂ receptor antagonist; Serotonin 5-HT_2A receptor antagonist
ATC code	None
Identifiers
IUPAC name 1-[2-[4-[(1R,3S)-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]piperazin-1-yl]ethyl]imidazolidin-2-one
CAS Number	96478-43-2
PubChem CID	65845
DrugBank	DB19936
ChemSpider	59257
UNII	4F39T8N10K
ChEMBL	ChEMBL73461
CompTox Dashboard (EPA)	DTXSID30242274
Chemical and physical data
Formula	C₂₄H₂₉FN₄O
Molar mass	408.521 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES C1CN(C(=O)N1)CCN2CCN(CC2)[C@@H]3C[C@H](C4=CC=CC=C34)C5=CC=C(C=C5)F
InChI InChI=1S/C24H29FN4O/c25-19-7-5-18(6-8-19)22-17-23(21-4-2-1-3-20(21)22)28-14-11-27(12-15-28)13-16-29-10-9-26-24(29)30/h1-8,22-23H,9-17H2,(H,26,30)/t22-,23+/m0/s1 Key:GHAMYXPEZSUOCU-XZOQPEGZSA-N

References

[1]
"Irindalone". AdisInsight. 1 August 1995. Retrieved 16 January 2026.
[2]
Smith HJ, Williams HJ (1 August 2002). Textbook of Drug Design and Discovery. CRC Press. ISBN 978-0-203-30137-1. Retrieved 16 January 2026. It was subsequently discovered that removal of the 'neuroleptic substituent' in the indan benzene ring (i.e. the trifluoromethyl group in 11.19), reduced the antagonism, whereas the 5-1-1 T 2 antagonism was retained. Concurrent replacement of the hydroxyethyl side chain with the more bulky I-ethyl-2imidazolidinone side chain, resulted in irindalone (11•20' Figure 11.7), which was a very potent and selective 5-HT antagonist. Irindalone was deveroped as a potential antihypertensive drug, but in 1989 the development was discontinued in Phase II for strategic reasons. Irindalone was, in contrast to tefludazine, developed as the pure (IR,3S)-enantiomer. This configuration of the I-piperazino-3- phenylindanes is generally associated with receptor antagonistic properties, while other stereoisomers are uptake inhibitors (see Section 11.3.3 and Figure 11.17).
[3]
Vilums M, Heuberger J, Heitman LH, IJzerman AP (November 2015). "Indanes--Properties, Preparation, and Presence in Ligands for G Protein Coupled Receptors". Medicinal Research Reviews. 35 (6): 1097–1126. doi:10.1002/med.21352. PMID 26018667. Substitutions at the piperazine ring were important for tuning central and peripheral activity, to the extent that a 1-ethyl-2-imidazolidinone moiety abolished neuroleptic activity and kept peripheral activity indicated by the compound's antihypertensive effects in rats. Additionally, the (+)-enantiomer was found to be much more active resulting in compound 60 (irindalone) (Fig. 15), with IC50 values of 3.4, 400, and 26 nM for 5HT2, DA, and α1 receptors, respectively
[4]
Baxter G, Kennett G, Blaney F, Blackburn T (March 1995). "5-HT2 receptor subtypes: a family re-united?". Trends in Pharmacological Sciences. 16 (3): 105–110. doi:10.1016/s0165-6147(00)88991-9. PMID 7792930.
[5]
Hyttel J, BøGesø K, LembøL HL, Larsen JJ, Meier E (1988). "Neurochemical profile in vitro of irindalone: A5-HT 2 -receptor antagonist". Drug Development Research. 15 (4): 389–404. doi:10.1002/ddr.430150406. ISSN 0272-4391.
[6]
Arnt J, Bøgesø KP, Boeck V, Christensen AV, Dragsted N, Hyttel J, et al. (1989). "In vivo pharmacology of irindalone, a 5-HT 2 receptor antagonist with predominant peripheral effects". Drug Development Research. 16 (1): 59–70. doi:10.1002/ddr.430160107. ISSN 0272-4391.
[7]
Hood SD, Argyropoulos SV, Nutt DJ (2003). "New directions in the treatment of anxiety disorders". Expert Opinion on Therapeutic Patents. 13 (4): 401–423. doi:10.1517/13543776.13.4.401. ISSN 1354-3776. Retrieved 16 January 2026.
[8]
"Abstracts from the XXIII CINP Congress, Montréal, June 23–27, 2002". The International Journal of Neuropsychopharmacology. 5 (S1). 2002. doi:10.1017/S1461145702003176. ISSN 1461-1457. Retrieved 16 January 2026.
[9]
Baxter GS, Murphy OE, Blackburn TP (May 1994). "Further characterization of 5-hydroxytryptamine receptors (putative 5-HT2B) in rat stomach fundus longitudinal muscle". British Journal of Pharmacology. 112 (1): 323–331. doi:10.1111/j.1476-5381.1994.tb13072.x. PMC 1910288. PMID 8032658.
[10]
Nichols DE, Schooler D, Yeung MC, Oberlender RA, Zabik JE (September 1984). "Unreliability of the rat stomach fundus as a predictor of hallucinogenic activity in substituted phenethylamines". Life Sciences. 35 (13): 1343–1348. doi:10.1016/0024-3205(84)90390-4. PMID 6482656.

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