Design, Synthesis, and Pharmacokinetics of a Bone-Targeting Dual-Action Prodrug for the Treatment of Osteoporosis

A dual-action
bone-targeting prodrug has been designed, synthesized,
and evaluated for in vitro and in vivo metabolic stability, in vivo
tissue distribution, and rates of release of the active constituents
after binding to bones through the use of differentially double-labeled
derivatives. The conjugate (general structure 7) embodies
the merger of a very potent and proven anabolic selective agonist
of the prostaglandin EP4 receptor, compound 5, and alendronic
acid, a potent inhibitor of bone resorption, optimally linked through
a differentially hydrolyzable linker unit, N-4-carboxymethylphenyl-methyloxycarbonyl-leucinyl-argininyl-para-aminophenylmethylalcohol (Leu-Arg-PABA). Optimized
conjugate 16 was designed so that esterase activity will
liberate 5 and cathepsin K cleavage of the Leu-Arg-PABA
element will liberate alendronic acid. Studies with doubly radiolabeled 16 provide a proof-of-concept for the use of a cathepsin K
cleavable peptide-linked conjugate for targeting of bisphosphonate
prodrugs to bone and slow release liberation of the active constituents
in vivo. Such conjugates are potential therapies for the treatment
of bone disorders such as osteoporosis.