Chemistry:Irindalone

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Irindalone (INN; 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-HT2A and 5-HT2C 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-HT2B 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-HT2C receptor blockade and enhance antidepressant efficacy.[7][8]

See also

  • Serotonin 5-HT2A receptor antagonist

References

  1. ↑ "Irindalone". 1 August 1995. https://adisinsight.springer.com/drugs/800000378. 
  2. ↑ 2.0 2.1 Textbook of Drug Design and Discovery. CRC Press. 1 August 2002. ISBN 978-0-203-30137-1. https://books.google.com/books?id=ZjzdazsyRVoC&pg=PA347. 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. ↑ 3.0 3.1 3.2 "Indanes--Properties, Preparation, and Presence in Ligands for G Protein Coupled Receptors". Medicinal Research Reviews 35 (6): 1097–1126. November 2015. 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. ↑ 4.0 4.1 "5-HT2 receptor subtypes: a family re-united?". Trends in Pharmacological Sciences 16 (3): 105–110. March 1995. doi:10.1016/s0165-6147(00)88991-9. PMID 7792930. 
  5. ↑ 5.0 5.1 5.2 5.3 "Neurochemical profile in vitro of irindalone: A5-HT 2 -receptor antagonist". Drug Development Research 15 (4): 389–404. 1988. doi:10.1002/ddr.430150406. ISSN 0272-4391. 
  6. ↑ 6.0 6.1 6.2 "In vivo pharmacology of irindalone, a 5-HT 2 receptor antagonist with predominant peripheral effects". Drug Development Research 16 (1): 59–70. 1989. doi:10.1002/ddr.430160107. ISSN 0272-4391. 
  7. ↑ 7.0 7.1 "New directions in the treatment of anxiety disorders". Expert Opinion on Therapeutic Patents 13 (4): 401–423. 2003. doi:10.1517/13543776.13.4.401. ISSN 1354-3776. http://www.tandfonline.com/doi/full/10.1517/13543776.13.4.401. Retrieved 16 January 2026. 
  8. ↑ 8.0 8.1 "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. https://academic.oup.com/ijnp/article-lookup/doi/10.1017/S1461145702003176. Retrieved 16 January 2026. 
  9. ↑ "Further characterization of 5-hydroxytryptamine receptors (putative 5-HT2B) in rat stomach fundus longitudinal muscle". British Journal of Pharmacology 112 (1): 323–331. May 1994. doi:10.1111/j.1476-5381.1994.tb13072.x. PMID 8032658. 
  10. ↑ "Unreliability of the rat stomach fundus as a predictor of hallucinogenic activity in substituted phenethylamines". Life Sciences 35 (13): 1343–1348. September 1984. doi:10.1016/0024-3205(84)90390-4. PMID 6482656. 



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