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

Abstract

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.

Innovative Linker Strategies for Tumor‐Targeted Drug Conjugates

“…tubulin binderso rD NA-damaging agents), as well as by modifying the drug loading onto the carrier.T he drug'sp hysical-chemical properties also impact on the construct activity:l ipophilic payloads diffuse rapidly through the cell membrane, enablingw idespread cell killing through the so-called "bystander effect", [4] whereas hydrophilic drugs often show low off-target toxicities. [5] Noteworthy,w hilethis research field has historically found widespread application in oncology (due to the medical need for potent cytotoxic agentsw ith improvedt herapeutic indexes), the preparation of targeted formulations and conjugatesh as also been recently proposed for other illnesses, such as bacterial infections, [6] osteoporosis, [7] bone fractures, [8] rheumatoid arthritis, [9] and other inflammatory diseases. [10] Among the structuralc omponents of tumor-targetingd evices, the carrier is the key regulator of the pharmacokinetic properties, since its size and structural features modulate the circulatory half-life,e xtravasationr ates, and residence time in the tumor ande xcretion.…”

Cathepsin-sensitive nanoscale drug delivery systems for cancer therapy and other diseases

“…In addition, there are several limitations associated with the systemic administration of drugs for bone treatment and bone-related diseases such as poor drug uptake at the target site, potential systemic toxicity as well as suboptimal efficacy [149]. Interestingly, there are examples in the literature describing Cathepsin-sensitive polymer conjugates for bone targeting purposes [151][152][153][154]. Therefore, drug delivery systems targeted towards bones can be adapted to bone diseases where the drug can be selectively delivered with minimal side effects [155].…”

Targeting therapeutics to bone by conjugation with bisphosphonates

“…In a recent study, another EP4 agonist-alendronate prodrug conjugate (6) was reported [36] where the two drugs were linked via a peptide linker (Figure 3). The peptide linker was based on Cbz-Leu-Phe-(7-amino-4-methylcoumarin), a known dipeptide substrate of cathepsin K, the proteolytic enzyme secreted by bone-resorbing osteoclasts.…”

“…Bone targeting prodrug conjugate liberating alendronate by action of cathepsin K [36] and 53 % over 24 hrs. Nonetheless the dual labelled conjugate was dosed to rats and notably, the ratio of labels found in the blood and liver were essentially the same as dosed, suggesting the conjugate was largely intact until eliminated.…”