Design, Synthesis, Pharmacokinetics, and Biodistribution of a Series of Bone-Targeting EP4 Receptor Agonist Prodrugs for Treatment of Osteoporosis and Other Bone Conditions

Peer reviewed: 
Yes, item is peer reviewed.
Scholarly level: 
Faculty/Staff
Final version published as: 

Thévenin, M., Chen, G., Kantham, S., Sun, C., Glogauer, M., & Young, R. N. (2021). Design, Synthesis, Pharmacokinetics, and Biodistribution of a Series of Bone-Targeting EP4 Receptor Agonist Prodrugs for Treatment of Osteoporosis and Other Bone Conditions. ACS Pharmacology & Translational Science. https://doi.org/10.1021/acsptsci.1c00027.

Date created: 
2021-03-10
Identifier: 
DOI: 10.1021/acsptsci.1c00027
Keywords: 
Prodrug
Bisphosphonate
Bone-targeting
EP4 receptor
Agonist
Anabolic
Pharmacokinetics
Abstract: 

A series of bone-targeting EP4 receptor agonist conjugate pro-drugs were prepared wherein a potent EP4 receptor agonist was bound to a biologically inactive, bisphosphonate-based bone-targeting moiety. Single and double radiolabeled conjugates were synthesized and were shown to be stable in blood, to be rapidly eliminated from the bloodstream and to be effectively taken up into bone in vivo after intravenous dosing. From these preliminary studies a preferred conjugate 4 (also known as C3 and Mes-1007) was selected for follow up bio-distribution and elimination studies. Double radiolabeled conjugate 4 was found to partition largely to liver and bones and both labels were eliminated from liver at the same rate indicating the conjugate was eliminated intact. Quantification of the labels in bones indicated that free EP4 agonist (EP4a)(2a) was released from the bone-bound 4 with a half-time of about 7 days. When dosed orally, the radiolabeled 4 was not absorbed and passed through the gastrointestinal tract essentially unchanged and only traces of radiolabel were found in liver, blood or bones. 4 was found to bind rapidly and completely to powdered bone mineral or to various forms of calcium phosphate to form a stable matrix suitable for implant and that could made into powders or solid forms and be sterilized without decomposition or release of 4. Basic hydrolysis released free EP4 agonist 2a quantitatively from the material.

Description: 

The full text of this paper will be available in March, 2022 due to the embargo policies of ACS Pharmacology & Translational Science. Contact summit@sfu.ca to enquire if the full text of the accepted manuscript can be made available to you.

Language: 
English
Document type: 
Article
Rights: 
Rights remain with the authors.
Sponsor(s): 
Canadian Institutes of Health Research (CIHR)
Natural Sciences and Engineering Research Council of Canada (NSERC)
Canada Foundation for Innovation (CFI)
British Columbia Government Leading Edge Endowment Fund
Simon Fraser University
University of Toronto
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