Synthesis and characterization of a new generation of bone targeting anabolic prodrugs

Prostaglandin E2 stimulates bone formation in vivo and exerts its effects through the EP4 receptor. Unfortunately prostaglandin E2 and agonists for the EP4 receptor also cause unacceptable systemic side effects which have limited their clinical use as anabolic agents. We developed novel bone-targeting prodrugs that can deliver EP4 agonists selectively to bone and liberate active drug slowly in situ to effect bone formation while avoiding the side effects. These prodrugs rely on enzyme activity in the bone to liberate the drug and it is not clear if active drug liberation will be replicated in humans. The subject of this project will be to synthesize a new class of prodrugs designed to liberate the active EP4 drug spontaneously and thus do not require enzymes for hydrolysis. Preliminary studies identified several candidates and we will now scale up the synthesis (including radiolabelled prodrugs) and test these compounds to demonstrate that they bind to bones in vitro and in vivo, liberate the active drug in vivo with a predictable and consistent half-life and are effciacious. Several analogs will be tested and the optimal release rate of 200 hr (suitable for once-weekly dosing) will be the goal.

Faculty Supervisor:

Robert Britton;Robert Young

Student:

Srivinas Kantham

Partner:

Mesentech Inc

Discipline:

Chemistry

Sector:

Professional, scientific and technical services

University:

Program: