Design and synthesis of novel bone-targeting dual-action pro-drugs for the treatment and reversal of osteoporosis

Bioorg Med Chem. 2012 Mar 15;20(6):2131-40. doi: 10.1016/j.bmc.2012.01.024. Epub 2012 Jan 31.


There is an important medical need for effective therapies to redress the general bone loss associated with advanced osteoporosis. Prostaglandin E(2) and related EP4 receptor agonists have been shown to stimulate bone regrowth but their use has been limited by systemic side effects. Herein is described the design and synthesis of novel dual-action bone-targeting conjugate pro-drugs where two classes of active agents, a bone growth stimulating prostaglandin E(2) EP4 receptor subtype agonist (5 or 6) and a bone resorption inhibitor bisphosphonate, alendronic acid (1), are coupled using metabolically labile carbamate or 4-hydroxyphenylacetic acid based linkers. Radiolabelled conjugates 9, 11a/b and 25 were synthesized and evaluated in vivo in rats for uptake of the conjugate into bone and subsequent release of the EP4 agonists over time. While conjugate 11a/b was taken up (9.0% of initial dose) but not released over two weeks, conjugates 9 and 25 were absorbed at 9.4% and 5.9% uptake of the initial dose and slowly released with half-lives of approximately 2 weeks and 5 days respectively. These conjugates were well tolerated and offer potential for sustained release and dual synergistic activity through their selective bone targeting and local release of the complimentary active components.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alendronate / analogs & derivatives*
  • Alendronate / chemical synthesis
  • Alendronate / pharmacokinetics
  • Alendronate / pharmacology*
  • Animals
  • Bone Density Conservation Agents / chemical synthesis
  • Bone Density Conservation Agents / chemistry*
  • Bone Density Conservation Agents / pharmacokinetics
  • Bone Density Conservation Agents / pharmacology*
  • Bone and Bones / drug effects
  • Bone and Bones / metabolism
  • Drug Design
  • Female
  • Osteoporosis / drug therapy
  • Osteoporosis / metabolism
  • Phenylacetates / chemistry
  • Prodrugs / chemical synthesis
  • Prodrugs / chemistry*
  • Prodrugs / pharmacokinetics
  • Prodrugs / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Prostaglandin E, EP4 Subtype / agonists*
  • Receptors, Prostaglandin E, EP4 Subtype / metabolism


  • Bone Density Conservation Agents
  • Phenylacetates
  • Prodrugs
  • Receptors, Prostaglandin E, EP4 Subtype
  • 4-hydroxyphenylacetic acid
  • Alendronate