ACD856

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ACD856
Clinical data
Other namesACD-856
Routes of
administration 		Oral [1] [2]
Drug class Tropomyosin receptor kinase TrkA, TrkB, and TrkC positive allosteric modulator [1] [3] [2] [4]
Pharmacokinetic data
Elimination half-life ~19 hours [5]

ACD856, or ACD-856, is a tropomyosin receptor kinase TrkA, TrkB, and TrkC positive allosteric modulator which is under development for the treatment of Alzheimer's disease, depressive disorders, sleep disorders, and traumatic brain injuries. [1] [3] [2] [5] [6] [4] It is taken by mouth. [1] [2]

Contents

Pharmacology

The drug potentiates the tropomyosin receptor kinases TrkA, TrkB, and TrkC with EC50 Tooltip half-maximal effective concentration values of 382 nM, 295 nM, and ~330 nM, respectively. [2] [4] As a positive allosteric modulator of TrkA and TrkB, ACD856 potentiates the effects of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). [6] [2] [7]

In addition to the tropomyosin receptor kinases, ACD856 is also a similarly potent positive allosteric modulator of certain other receptor tyrosine kinases, including the insulin-like growth factor 1 receptor (IGF1R) and the fibroblast growth factor receptor 1 (FGFR1). [4] However, its efficacies at the IGF1R and FGFR1 were much lower than at the TrkA, TrkB, and TrkC. [4]

In animals, ACD856 has been found to reverse scopolamine- and dizocilpine (MK-801)-induced memory impairment, to improve age-related memory deficits, and to have sustained antidepressant-like activity. [5] [2] [7] [8] [4] It has also been reported to possess neuroprotective properties. [5] [7]

In humans, the drug has been shown to cross the blood–brain barrier and to induce dose-dependent changes in electroencephalogram parameters. [5] [2] [9] No significant tolerability or safety concerns have been identified in preclinical research or phase 1 clinical trials. [10] The drug's clinical pharmacokinetics have been characterized and its elimination half-life is approximately 19 hours. [5] [11] [9]

Chemistry

The chemical structure of ACD856 has not yet been disclosed as of 2024, but the structure of its predecessor ponazuril (ACD855) is known and both ponazuril and ACD856 have been described as triazinetriones. [5] [7]

History

It was discovered through the use of high-throughput screening of 25,000 compounds. [5] [2] [4] Toltrazuril and ponazuril (ACD855), two veterinary antiparasitic agents, were identified as possessing Trk-potentiating activity with this screen in 2013. [2] [5] [4] ACD856 was derived via structural optimization of these compounds. [2] [5] In the case of ponazuril, this drug was said to have had too long of an elimination half-life to allow for development for use in humans. [11] ACD856 was first described in the scientific literature by 2021. [4] [12]

Clinical trials

As of May 2024, ACD856 is in phase 1 clinical trials for Alzheimer's disease and is in the preclinical stage of development for depressive disorders, sleep disorders, and traumatic brain injuries. [1] [3] [2] Two phase 1 trials have been completed. [10] A phase 2 clinical trial for Alzheimer's disease is being planned as of May 2024. [1] The drug is under development by AlzeCure Pharma AB. [1] [3] [2]

Related Research Articles

<span class="mw-page-title-main">Ampakine</span> Subgroup of AMPA receptor positive allosteric modulators

Ampakines or AMPAkines are a subgroup of AMPA receptor positive allosteric modulators with a benzamide or closely related chemical structure. They are also known as "CX compounds". Ampakines take their name from the AMPA receptor (AMPAR), a type of ionotropic glutamate receptor with which the ampakines interact and act as positive allosteric modulators (PAMs) of. Although all ampakines are AMPAR PAMs, not all AMPAR PAMs are ampakines.

<span class="mw-page-title-main">CX717</span> Ampakine

CX717 is an ampakine compound created by Christopher Marrs and Gary Rogers in 1996 at Cortex Pharmaceuticals. It affects the neurotransmitter glutamate, with trials showing the drug improves cognitive functioning and memory.

<span class="mw-page-title-main">Tropomyosin receptor kinase A</span> Protein-coding gene in the species Homo sapiens

Tropomyosin receptor kinase A (TrkA), also known as high affinity nerve growth factor receptor, neurotrophic tyrosine kinase receptor type 1, or TRK1-transforming tyrosine kinase protein is a protein that in humans is encoded by the NTRK1 gene.

<span class="mw-page-title-main">Tropomyosin receptor kinase B</span> Protein and coding gene in humans

Tropomyosin receptor kinase B (TrkB), also known as tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the NTRK2 gene. TrkB is a receptor for brain-derived neurotrophic factor (BDNF). The standard pronunciation for this protein is "track bee".

<span class="mw-page-title-main">Tropomyosin receptor kinase C</span> Protein-coding gene in the species Homo sapiens

Tropomyosin receptor kinase C (TrkC), also known as NT-3 growth factor receptor, neurotrophic tyrosine kinase receptor type 3, or TrkC tyrosine kinase is a protein that in humans is encoded by the NTRK3 gene.

<span class="mw-page-title-main">CX614</span> Chemical compound

CX-614 is an ampakine drug developed by Cortex Pharmaceuticals. It has been investigated for its effect on AMPA receptors.

Trk receptors are a family of tyrosine kinases that regulates synaptic strength and plasticity in the mammalian nervous system. Trk receptors affect neuronal survival and differentiation through several signaling cascades. However, the activation of these receptors also has significant effects on functional properties of neurons.

<span class="mw-page-title-main">LY-503430</span> Chemical compound

LY-503430 is an AMPA receptor positive allosteric modulator developed by Eli Lilly.

<span class="mw-page-title-main">Ponazuril</span> Chemical compound

Ponazuril (INN), sold by Merial, Inc., now part of Boehringer Ingelheim, under the trade name Marquis® , is a drug currently approved for the treatment of equine protozoal myeloencephalitis (EPM) in horses, caused by coccidia Sarcocystis neurona. Veterinarians have been preparing a formulary version of the medication for use in small animals such as cats, dogs, and rabbits against coccidia as an intestinal parasite. Coccidia treatment in small animals is far shorter than treatment for EPM. Along with its analogue ACD856, ponazuril is a positive allosteric modulator of the tropomyosin receptor kinases TrkA and TrkB.

<span class="mw-page-title-main">Deoxygedunin</span> Chemical compound

Deoxygedunin, or 14,15-deoxygedunin, is a tetranortriterpenoid isolated from the Indian neem tree a plant that has been in traditional Indian medicine since ancient times as a remedy for various ailments.

<span class="mw-page-title-main">Cyclotraxin B</span> Chemical compound

Cyclotraxin B (CTX-B) is a small (1200 Da) cyclic peptide and highly potent (IC50  = 0.30 nM), selective, and non-competitive antagonist or negative allosteric modulator of TrkB, the main receptor of brain-derived neurotrophic factor (BDNF). CTX-B was originally developed by Cazorla M. and colleagues at Université Paris and Inserm in 2010, mimicking a specific structural loop in BDNF known for its functional selectivity. Cyclotraxin-B's name originates from Cyclic trk inhibitor B.

<span class="mw-page-title-main">R7 (drug)</span> Chemical compound

R7 is a small-molecule flavonoid and orally active, potent, and selective agonist of the tropomyosin receptor kinase B (TrkB) – the main signaling receptor for the neurotrophin brain-derived neurotrophic factor (BDNF) – which is under development for the treatment of Alzheimer's disease. It is a structural modification and prodrug of tropoflavin (7,8-DHF) with improved potency and pharmacokinetics, namely oral bioavailability and duration.

<span class="mw-page-title-main">Mibampator</span> Chemical compound

Mibampator is a positive allosteric modulator (PAM) of the AMPA receptor (AMPAR), an ionotropic glutamate receptor, which was under development by Eli Lilly for the treatment of agitation/aggression in Alzheimer's disease but was never marketed. It reached phase II clinical trials prior to the discontinuation of its development.

<span class="mw-page-title-main">Tulrampator</span> Chemical compound

Tulrampator is a positive allosteric modulator (PAM) of the AMPA receptor (AMPAR), an ionotropic glutamate receptor, which is under development by RespireRx Pharmaceuticals and Servier for the treatment of major depressive disorder, Alzheimer's disease, dementia, and mild cognitive impairment. Tulrampator was in phase II clinical trial for depression, but failed to show superiority over placebo. There are also phase II clinical trials for Alzheimer's disease and phase I trials for dementia and mild cognitive impairment.

<span class="mw-page-title-main">R13 (drug)</span> Chemical compound

R13 is a small-molecule flavonoid and orally active, potent, and selective agonist of the tropomyosin receptor kinase B (TrkB) – the main signaling receptor for the neurotrophin brain-derived neurotrophic factor (BDNF) – which is under development for the potential treatment of Alzheimer's disease. It is a structural modification and prodrug of tropoflavin (7,8-DHF) with improved potency and pharmacokinetics, namely oral bioavailability and duration. The compound is a replacement for the earlier tropoflavin prodrug R7 and has similar properties to it. It was developed because while R7 displayed a good drug profile in animal studies, it showed almost no conversion into tropoflavin in human liver microsomes. In contrast to R7, R13 is readily hydrolyzed into tropoflavin in human liver microsomes.

<span class="mw-page-title-main">Mevidalen</span> Chemical compound

Mevidalen (LY-3154207) is a dopaminergic drug which is under development for the treatment of Lewy body disease, including those with Parkinson's disease.

<span class="mw-page-title-main">Glovadalen</span> D1 receptor positive allosteric modulator under development for Parkinsons disease

Glovadalen (developmental code name UCB-0022) is a dopamine D1 receptor positive allosteric modulator which is under development for the treatment of Parkinson's disease. It has been found to potentiate the capacity of dopamine to activate the D1 receptor by 10-fold in vitro with no actions on other dopamine receptors. As of May 2024, glovadalen is in phase 2 clinical trials for this indication. The drug is under development by UCB Biopharma. It is described as an orally active, centrally penetrant small molecule.

<span class="mw-page-title-main">Traneurocin</span> Neuroprotective drug

Traneurocin, also known as cycloprolylglycine (CPG), is a racetam-like drug which is under development for the treatment of COVID-19, Alzheimer's disease, fragile X syndrome, Rett syndrome, major depressive disorder, and other neurological disorders. In the case of COVID-19, it is specifically being developed for treatment of COVID-19-induced neuropathy.

References

  1. 1 2 3 4 5 6 7 "ACD 856". AdisInsight. Springer Nature Switzerland AG. 17 May 2024. Retrieved 23 October 2024.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 "ACD856". ALZFORUM. 19 December 2023. Retrieved 23 October 2024.
  3. 1 2 3 4 "Delving into the Latest Updates on ACD-856 with Synapse". Synapse. 12 October 2024. Retrieved 23 October 2024.
  4. 1 2 3 4 5 6 7 8 9 Dahlström M, Madjid N, Nordvall G, Halldin MM, Vazquez-Juarez E, Lindskog M, et al. (July 2021). "Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction". Cells. 10 (8): 1871. doi: 10.3390/cells10081871 . PMC   8391421 . PMID   34440640.
  5. 1 2 3 4 5 6 7 8 9 10 Forsell P, Parrado Fernández C, Nilsson B, Sandin J, Nordvall G, Segerdahl M (July 2024). "Positive Allosteric Modulators of Trk Receptors for the Treatment of Alzheimer's Disease". Pharmaceuticals. 17 (8): 997. doi: 10.3390/ph17080997 . PMC   11357672 . PMID   39204102.
  6. 1 2 Wang D, Lang ZC, Wei SN, Wang W, Zhang H (2 May 2024). "Targeting brain-derived neurotrophic factor in the treatment of neurodegenerative diseases: A review". Neuroprotection. 2 (2). Wiley: 67–78. doi: 10.1002/nep3.43 . ISSN   2770-7296. ACD856 is an innovative allosteric modulator that positively affects all Trk receptors, amplifying their kinase activity. Subsequently, it potentiates the effect of BDNF or nerve growth factor (NGF) on neuronal survival, function, and plasticity of synapses. The finished phase I study showed that ACD856 passed the blood‐brain barrier and induced dose‐dependent treatment‐related alterations in quantitative electroencephalogram parameters with good safety.141,142
  7. 1 2 3 4 Parrado Fernandez C, Juric S, Backlund M, Dahlström M, Madjid N, Lidell V, et al. (July 2023). "Neuroprotective and Disease-Modifying Effects of the Triazinetrione ACD856, a Positive Allosteric Modulator of Trk-Receptors for the Treatment of Cognitive Dysfunction in Alzheimer's Disease". International Journal of Molecular Sciences. 24 (13): 11159. doi: 10.3390/ijms241311159 . PMC   10342804 . PMID   37446337.
  8. ↑ Madjid N, Lidell V, Nordvall G, Lindskog M, Ögren SO, Forsell P, et al. (August 2023). "Antidepressant effects of novel positive allosteric modulators of Trk-receptor mediated signaling - a potential therapeutic concept?". Psychopharmacology. 240 (8): 1789–1804. doi:10.1007/s00213-023-06410-x. PMC   10349764 . PMID   37394539.
  9. 1 2 Önnestam K, Nilsson B, Rother M, Rein-Hedin E, Bylund J, Anderer P, et al. (2023). "Safety, Tolerability, Pharmacokinetics and Quantitative Electroencephalography Assessment of ACD856, a Novel Positive Allosteric Modulator of Trk-Receptors Following Multiple Doses in Healthy Subjects". The Journal of Prevention of Alzheimer's Disease. 10 (4): 778–789. doi:10.14283/jpad.2023.89. PMID   37874100.
  10. 1 2 Nordvall G, Forsell P, Sandin J (October 2022). "Neurotrophin-targeted therapeutics: A gateway to cognition and more?". Drug Discovery Today. 27 (10): 103318. doi: 10.1016/j.drudis.2022.07.003 . PMID   35850433.
  11. 1 2 Nilsson B, Bylund J, Halldin MM, Rother M, Rein-Hedin E, Önnestam K, et al. (May 2024). "ACD856, a novel positive allosteric modulator of Trk receptors, single ascending doses in healthy subjects: Safety and pharmacokinetics". European Journal of Clinical Pharmacology. 80 (5): 717–727. doi:10.1007/s00228-024-03645-1. PMC   11001683 . PMID   38353689.
  12. ↑ Nordvall G, Madjid N, Backlund M, Halldin M, Rother M, Nilsson B, et al. (2021). "ACD856: A novel positive allosteric modulator of Trk-signaling in clinical development for the treatment of Alzheimer's disease". Alzheimer's & Dementia. 17 (S9). Wiley. doi: 10.1002/alz.057730 . ISSN   1552-5260.
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