Abstract
Purpose
There is growing interest in seeking pharmacological activation of neurolysin (Nln) for stroke treatment. Discovery of central nervous system drugs remains challenging due to the protection of the blood-brain barrier (BBB). The previously reported peptidomimetic Nln activators display unsatisfactory BBB penetration. Herein, we investigate the next generation of non-peptidomimetic Nln activators with high BBB permeability.
Methods
A BBB-mimicking model was used to evaluate their in vitro BBB permeability. Protein binding, metabolic stability, and efflux assays were performed to determine their unbound fraction, half-lives in plasma and brains, and dependence of BBB transporter P-glycoprotein (P-gp). The in vivo pharmacokinetic profiles were elucidated in healthy and stroke mice.
Results
Compounds KS52 and KS73 out of this generation exhibit improved peptidase activity and BBB permeability compared to the endogenous activator and previous peptidomimetic activators. They show reasonable plasma and brain protein binding, improved metabolic stability, and independence of P-gp-mediated efflux. In healthy animals, they rapidly distribute into brains and reach peak levels of 18.69% and 12.10% injected dose (ID)/ml at 10 min. After 4 h, their total brain concentrations remain 7.78 and 12.34 times higher than their A50(minimal concentration required for enhancing 50% peptidase activity). Moreover, the ipsilateral hemispheres of stroke animals show comparable uptake to the corresponding contralateral hemispheres and healthy brains.
Conclusions
This study provides essential details about the pharmacokinetic properties of a new generation of potent non-peptidomimetic Nln activators with high BBB permeability and warrants the future development of these agents as potential neuroprotective pharmaceutics for stroke treatment.
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Data Availability
The authors confirm that the data supporting the findings of this study are available within the article.
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Funding
This study was supported by NIH grant R01NS106879 to P.C.T., V.T.K., and T.J.A.
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The authors Y.Z., S.J., S.K., S.H.E., S.N., P.C.T., V.T.K., and T.J.A. have a U.S. Patent Application for compounds KS52 and KS73.
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Zhang, Y., Sharma, S., Jonnalagadda, S. et al. Discovery of the Next Generation of Non-peptidomimetic Neurolysin Activators with High Blood-Brain Barrier Permeability: a Pharmacokinetics Study in Healthy and Stroke Animals. Pharm Res 40, 2747–2758 (2023). https://doi.org/10.1007/s11095-023-03619-5
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DOI: https://doi.org/10.1007/s11095-023-03619-5