LY-2624803

Last updated

LY-2624803
LY-2624803.svg
Clinical data
Other namesLY2624803; HY-10275; HY10275
Routes of
administration 		Oral [1]
Drug class Histamine H1 receptor antagonist; Serotonin 5-HT2A receptor antagonist; Sedative; Hypnotic
ATC code
  • None
Identifiers
  • 3-(4-benzo[b][1,4]benzoxazepin-6-ylpiperazin-1-yl)-2,2-dimethylpropanoic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
Chemical and physical data
Formula C22H25N3O3
Molar mass 379.460 g·mol−1
3D model (JSmol)
  • CC(C)(CN1CCN(CC1)C2=NC3=CC=CC=C3OC4=CC=CC=C42)C(=O)O
  • InChI=1S/C22H25N3O3/c1-22(2,21(26)27)15-24-11-13-25(14-12-24)20-16-7-3-5-9-18(16)28-19-10-6-4-8-17(19)23-20/h3-10H,11-15H2,1-2H3,(H,26,27)
  • Key:UEFWDVMEDFCHGW-UHFFFAOYSA-N

LY-2624803, also known as HY-10275, is a dual histamine H1 receptor and serotonin 5-HT2A receptor antagonist which was under development for the treatment of insomnia but was never marketed. [1] [2] [3] It is taken orally. [1]

Contents

Pharmacology

The drug is described as a high-affinity highly selective histamine H1 receptor inverse agonist with additional strong serotonin 5-HT2A receptor antagonism or inverse agonism. [2] [4] [5] The precise balance of these activities has not been disclosed. [6] It was found to dose-dependently increase slow wave sleep in animals. [5] In a phase 2 clinical trial, the drug was found to significantly reduce wake after sleep onset (WASO) (by 35 minutes at 1 mg and by 62 minutes at 3 mg) as well as to reduce sleep onset latency in humans. [2] No next-day residual fatigue was observed. [2] In terms of chemical structure, it is an analogue of tricyclic compounds like quetiapine and amoxapine. [7] [3]

Development

LY-2624803 was under development by Eli Lilly and Hypnion. [1] [3] [2] Its development was discontinued in 2011. [1] [8] [9] The drug reached phase 2 trials prior to the discontinuation of its development. [1] [10] Besides doxepin (Silenor; SO-101) and esmirtazapine (ORG-50081), it was one of the only histamine H1 receptor antagonists to have reached phase 2 trials for treatment of insomnia. [11] [4]

See also

References

  1. 1 2 3 4 5 6 "LY 2624803". AdisInsight. 5 November 2023. Retrieved 6 October 2025.
  2. 1 2 3 4 5 Sullivan SS, Guilleminault C (September 2009). "Emerging drugs for insomnia: new frontiers for old and novel targets". Expert Opinion on Emerging Drugs. 14 (3): 411–422. doi:10.1517/14728210903171948. PMID   19708818. 4.3.2 LY-2624803: Another highly-selective histamine H1 receptor antagonist that also has strong 5-HT2A inhibition, LY-2624803, is under development by Lilly for the treatment of chronic insomnia. Currently in Phase II trials, this agent was studied in a double-blind, randomized, proof-of-concept trial of 52 patients with transient insomnia. Doses of 1 and 3 mg significantly decreased WASO by 35 and 62 min, respectively. A secondary end point of improved sleep latency was also demonstrated. There were no drug-related adverse events, including next-day residual fatigue [72]. While this agent is expected to launch in 2012 – 2015, the current Phase II trial, a randomized, double-blind, placebo-controlled, active agent-compared (zolpidem) crossover study, has been suspended until the investigation of a finding in an animal study can be completed [73].
  3. 1 2 3 Beaton G, Moree WJ (September 2010). "The expanding role of H1 antihistamines: a patent survey of selective and dual activity compounds 2005-2010". Expert Opinion on Therapeutic Patents. 20 (9): 1197–1218. doi:10.1517/13543776.2010.510516. PMID   20716024. Key examples shown in Figure 5 are compounds 40 -- 44. Compounds 40 and 43 (HY-2901) have been evaluated in some detail. Indeed, compound 43 was a key compound in the program [128]. This compound was replaced by the clinical compound HY-10275, a dual H1--5-HT2A antagonist for which the structure is yet to be disclosed [129]. [...] Hypnion was recently acquired by Eli Lilly and HY-10275 remains in the Eli Lilly clinical research portfolio in Phase II as LY-2624803 [131]. A Phase II trial in chronic insomnia was recently completed [132].
  4. 1 2 Abbas A, Roth BL (December 2008). "Pimavanserin tartrate: a 5-HT2A inverse agonist with potential for treating various neuropsychiatric disorders". Expert Opinion on Pharmacotherapy. 9 (18): 3251–3259. doi:10.1517/14656560802532707. PMID   19040345. Studies in rodents and humans have shown a robust increase of SWS by 5-HT 2A antagonists [38,39] . At present, there are three 5-HT 2A antagonists in Phase III trials for treating insomnia (eplivanserin, volinanserin, pruvanserin), and two inverse agonists in Phase II insomnia trials (APD125 and HY10275) [34] .
  5. 1 2 "Portico". Portico. Retrieved 6 October 2025. Researchers from Hypnion have developed a series of novel histamine H1 agonists to enhance and maintain natural sleep, highlighting HY-10275 for further study. HY-10275 acts as an inverse H1 agonist with nanomolar affinity and high selectivity for this receptor subtype. Preclinical studies in rats demonstrated that this compound is orally bioavailable and penetrates into brain tissue to significantly increase non-rapid eye movement (NREM) sleep (+25, +44 and +48 min at 1, 3 and 10 mg/kg p.o., respectively). Further analysis in rats, dogs and primates confirmed that HY-10275 lacks significant oxidative metabolites or interaction with cytochrome P450 enzymes. This compound is a good candidate for the management of sleep maintenance insomnia and has already completed phase I clinical trials (Edgar, D.M. et al. Sleep 2006, 29(Suppl.): Abst 0138).
  6. ↑ Teegarden BR, Al Shamma H, Xiong Y (2008). "5-HT(2A) inverse-agonists for the treatment of insomnia". Current Topics in Medicinal Chemistry. 8 (11): 969–976. doi:10.2174/156802608784936700. PMID   18673166. 3.9. HY-10275: Hypnion has recently completed a phase II trial for HY10275 (structure currently not disclosed), a compound with the dual mechanism of H1 inverse-agonism and 5-HT2A antagonism; the balance of the receptor activity has not been disclosed. The H1 antagonism should reduce the latency to sleep onset, giving this molecule the potential for a dual mechanism of action. In the phase II trial, 1 and 3 mg doses of HY-10275 showed positive results regarding wake after sleep onset compared to placebo in patients with transient insomnia [112]. Since the acquisition of Hypnion by Eli Lilly in 2007 no further information has been available regarding the clinical status of HY-10275.
  7. ↑ "1-Piperazinepropanoic acid, 4-dibenz(b,f)(1,4)oxazepin-11-yl-alpha,alpha-dimethyl-". PubChem. Retrieved 6 October 2025.
  8. ↑ Abad VC, Guilleminault C (September 2018). "Insomnia in Elderly Patients: Recommendations for Pharmacological Management". Drugs & Aging. 35 (9): 791–817. doi:10.1007/s40266-018-0569-8. PMID   30058034.
  9. ↑ Zisapel N (March 2015). "Current Phase II investigational therapies for insomnia". Expert Opinion on Investigational Drugs. 24 (3): 401–411. doi:10.1517/13543784.2015.987340. PMID   25423562.
  10. ↑ Sullivan S (September 2012). "Update on emerging drugs for insomnia". Expert Opinion on Emerging Drugs. 17 (3): 295–298. doi:10.1517/14728214.2012.693158. PMID   22920041.
  11. ↑ Equihua-Benítez AC, Guzmán-Vásquez K, Drucker-Colín R (July 2017). "Understanding sleep-wake mechanisms and drug discovery". Expert Opinion on Drug Discovery. 12 (7): 643–657. doi:10.1080/17460441.2017.1329818. PMID   28511597. The FDA approved TCA doxepin, when used at low doses (3 -6 mg) is a potent H1R antagonist. [44,46,54,82] There is at least one H1R antagonist that has reached phase 2 clinical trials: LY2624803. However, there are no open clinical trials for this drug since 2013. Another H1R antagonist, esmirtazapine, reached phase 3 clinical with promising results. Nonetheless, the pharmaceutical company dropped the development citing strategic reasons.
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