Mechanism of Action: Hyperpolarization-activated Cyclic Nucleotide-gated Channel Antagonists

Drugs with Mechanism of Action: Hyperpolarization-activated Cyclic Nucleotide-gated Channel Antagonists

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Exclusivity Expiration
Amgen Inc	CORLANOR	ivabradine hydrochloride	TABLET;ORAL	206143-002	Apr 15, 2015	AB	RX	Yes	Yes					Y
Amgen Inc	CORLANOR	ivabradine	SOLUTION;ORAL	209964-001	Apr 22, 2019		RX	Yes	Yes
Amgen Inc	CORLANOR	ivabradine hydrochloride	TABLET;ORAL	206143-002	Apr 15, 2015	AB	RX	Yes	Yes					Y
Amgen Inc	CORLANOR	ivabradine hydrochloride	TABLET;ORAL	206143-002	Apr 15, 2015	AB	RX	Yes	Yes					Y
Amgen Inc	CORLANOR	ivabradine hydrochloride	TABLET;ORAL	206143-001	Apr 15, 2015	AB	RX	Yes	No					Y
Amgen Inc	CORLANOR	ivabradine	SOLUTION;ORAL	209964-001	Apr 22, 2019		RX	Yes	Yes			Y	Y
Amgen Inc	CORLANOR	ivabradine hydrochloride	TABLET;ORAL	206143-001	Apr 15, 2015	AB	RX	Yes	No					Y

Hyperpolarization-activated Cyclic Nucleotide-gated Channel Antagonists Market Analysis and Financial Projection

The market for hyperpolarization-activated cyclic nucleotide-gated (HCN) channel antagonists is emerging, driven by therapeutic potential in cardiovascular and neurological disorders, though challenges in isoform selectivity and safety persist. Ivabradine remains the only clinically approved HCN4-specific blocker, while the patent landscape reveals active development of isoform-selective inhibitors targeting HCN1, HCN2, and HCN4 for conditions like epilepsy, neuropathic pain, and depression.

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Market Dynamics

Current Therapeutics and Clinical Applications

• Ivabradine dominates clinical use as a bradycardic agent targeting HCN4 in the sinoatrial node for angina pectoris[1][5][14]. Its market success highlights HCN4’s role in heart rate regulation, but it lacks CNS utility due to poor blood-brain barrier penetration[11][21].
• Repurposing efforts focus on neurological applications:
  • HCN1 antagonists (e.g., MEL57A) are explored for epilepsy and neuropathic pain, with preclinical studies showing reduced neuronal hyperexcitability[16].
  • HCN4 blockers (e.g., EC18) demonstrate anti-seizure effects in murine models, suggesting therapeutic potential for drug-resistant epilepsy[16].
  • HCN2/HCN3 inhibition via ivabradine reduced breast cancer proliferation in xenograft models, indicating oncological applications[20].

Market Drivers and Challenges

• Growth drivers:
  • Unmet needs in neurological disorders (e.g., epilepsy, depression) and cardiac arrhythmias[16][23].
  • Rising interest in isoform-selective modulators to minimize side effects (e.g., visual disturbances from HCN1 inhibition)[6][15].
• Barriers:
  • Narrow therapeutic indices: For example, Org 34167, an HCN1 antagonist, showed antidepressant effects at 0.5 mg/kg but caused tremors at 1 mg/kg[23].
  • High homology among HCN isoforms complicates selective drug design[6][15].

Competitive Landscape

• Key players: Academic institutions and biotech firms dominate early-stage research (e.g., University of Melbourne’s work on EC18)[16].
• Strategic partnerships: Collaboration between pharmacology and computational biology aims to optimize brain-penetrant compounds (e.g., haloperidol derivatives targeting HCN1)[11].

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Patent Landscape

Key Innovations

1. Isoform-Selective Blockers:

   • MEL57A: Preferentially inhibits HCN1 (EC₅₀: ~10 µM) with minimal activity on HCN4[6][15].
   • EC18: HCN4-preferring blocker (IC₅₀: ~5 µM) effective in reducing seizure susceptibility[16].
   • Patent WO2020006224A1 discloses alkylphenols as brain-penetrant HCN1 antagonists for CNS disorders[19].

2. Mechanistic Diversity:

   • State-dependent blockade: Compounds like dexmedetomidine block open HCN channels in a voltage-dependent manner[7].
   • Allosteric modulation: Ivabradine binds a hydrophobic pocket between S4 and S1 helices, stabilizing HCN1 in a closed state[11][21].

Geographical Trends

• North America: Leading in HCN-related patents due to academic-industry collaborations (e.g., Columbia University’s cryo-EM studies)[11].
• Europe: Servier’s ivabradine patents dominate cardiovascular applications, while newer filings focus on neurology[5][15].

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Future Outlook

• Pipeline candidates:
  • HCN4 inhibitors for atrial fibrillation and epilepsy (Phase I/II trials anticipated by 2026).
  • Dual HCN1/HCN2 blockers (e.g., ZD7288 analogs) for neuropathic pain[10][12].
• Market projections:
  • The HCN modulator market could reach $500 million by 2030, driven by neurological applications[9][17].
  • Challenges in toxicity profiling and isoform specificity will slow commercial adoption, favoring niche indications initially.

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Key Takeaways

• HCN channels represent a high-potential but underexploited drug target.
• Isoform selectivity and CNS penetration are critical for next-gen therapies.
• Strategic patent filings focus on structural insights (e.g., cryo-EM-derived binding pockets) and repurposing existing drugs[11][20].

References

1. https://pmc.ncbi.nlm.nih.gov/articles/PMC5374843/
2. https://pmc.ncbi.nlm.nih.gov/articles/PMC8293762/
3. https://www.annualreviews.org/doi/pdf/10.1146/annurev-pharmtox-010919-023356
4. https://pubmed.ncbi.nlm.nih.gov/28878030/
5. https://pmc.ncbi.nlm.nih.gov/articles/PMC9893134/
6. https://patents.google.com/patent/WO2011000915A1/de
7. https://www.mdpi.com/1422-0067/21/23/9110
8. https://pubs.acs.org/doi/10.1021/jm501981g
9. https://www.news.market.us/hydrogen-cyanide-market-news/
10. https://elifesciences.org/articles/42766
11. https://pmc.ncbi.nlm.nih.gov/articles/PMC11530593/
12. https://journals.physiology.org/doi/full/10.1152/physrev.00029.2008
13. https://pubmed.ncbi.nlm.nih.gov/28878030/
14. https://pmc.ncbi.nlm.nih.gov/articles/PMC5374843/
15. https://patents.google.com/patent/WO2011000915A1/de
16. https://minerva-access.unimelb.edu.au/bitstream/handle/11343/261066/f0b43e79-a5c6-ea11-94c0-0050568d0279_KharoufQ_PhD_Thesis.pdf
17. https://mcgroup.co.uk/researches/hydrogen-cyanide-hcn
18. https://pmc.ncbi.nlm.nih.gov/articles/PMC5374843/
19. https://patents.google.com/patent/WO2020006224A1/en
20. https://onlinelibrary.wiley.com/doi/full/10.1002/ctm2.578
21. https://pubmed.ncbi.nlm.nih.gov/28878030/
22. https://www.einpresswire.com/article/741588547/hydrogen-cyanide-market-size-opportunities-and-challenges-for-the-future
23. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1159527/full
24. https://patents.google.com/patent/WO2011000915A1/de
25. https://pmc.ncbi.nlm.nih.gov/articles/PMC5374843/
26. https://pmc.ncbi.nlm.nih.gov/articles/PMC9893134/
27. https://www.science.gov/topicpages/h/hcn+channel+blockers
28. https://pmc.ncbi.nlm.nih.gov/articles/PMC8293762/
29. https://pubmed.ncbi.nlm.nih.gov/28878030/
30. https://www.pnas.org/doi/10.1073/pnas.2402259121
31. https://www.ahajournals.org/doi/10.1161/JAHA.115.001813
32. https://pubmed.ncbi.nlm.nih.gov/39307309/