- Source: ACD856
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. It is taken by mouth.
Pharmacology
The drug potentiates the tropomyosin receptor kinases TrkA, TrkB, and TrkC with EC50Tooltip half-maximal effective concentration values of 382 nM, 295 nM, and ~330 nM, respectively. As a positive allosteric modulator of TrkA and TrkB, ACD856 potentiates the effects of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF).
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). However, its efficacies at the IGF1R and FGFR1 were much lower than at the TrkA, TrkB, and TrkC.
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. It has also been reported to possess neuroprotective properties.
In humans, the drug has been shown to cross the blood–brain barrier and to induce dose-dependent changes in electroencephalogram parameters. No significant tolerability or safety concerns have been identified in preclinical research or phase 1 clinical trials. The drug's clinical pharmacokinetics have been characterized and its elimination half-life is approximately 19 hours.
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.
History
It was discovered through the use of high-throughput screening of 25,000 compounds. Toltrazuril and ponazuril (ACD855), two veterinary antiparasitic agents, were identified as possessing Trk-potentiating activity with this screen in 2013. ACD856 was derived via structural optimization of these compounds. 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. ACD856 was first described in the scientific literature by 2021.
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. Two phase 1 trials have been completed. A phase 2 clinical trial for Alzheimer's disease is being planned as of May 2024. The drug is under development by AlzeCure Pharma AB.
References
Kata Kunci Pencarian:
- ACD856
- Ponazuril
- List of investigational antidepressants
- Tropomyosin receptor kinase B
- Tropomyosin receptor kinase A
