How to blast osteoblasts? Novel dicarba analogues of amylin-(1-8) to treat osteoporosis

Bioorg Med Chem. 2012 Oct 15;20(20):6011-8. doi: 10.1016/j.bmc.2012.08.053. Epub 2012 Sep 7.


When administered in vivo, amylin (1-8) stimulates osteoblast proliferation increasing bone volume and bone strength. The native cyclic octapeptide amylin (1-8) is unstable, however, it provides an attractive framework for the creation of more stable, orally active synthetic analogues using various peptidomimetic techniques. On-resin ring closing metathesis (RCM) on the olefinic side chains of allylglycine residues and lysine moieties functionalized with an allyloxycarbonyl (Alloc) group, was used to prepare novel carba-bridged surrogates of the disulfide bridge between Cys/2 and Cys/7 in amylin-(1-8). Commercially available N(α)-Fmoc N(ε)-Alloc protected lysine was used as a convenient substrate for Grubbs' ring closing metathesis. Analogues of amylin-(1-8) prepared by cyclization of allylglycine residues that also contained proline residues at either position 4 or 6, or both, were also prepared to investigate the effect of proline as a 'kink-inducing' residue on the efficiency of the RCM reaction. Of the nine novel alkene-bridged analogues prepared, five showed promising biological activity in a proliferation study in primary foetal rat osteoblasts at physiological concentrations. Two of these analogues were chosen for further in vivo evaluation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allylglycine / chemistry
  • Amino Acid Sequence
  • Animals
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cyclization
  • Disulfides / chemistry
  • Islet Amyloid Polypeptide / chemistry*
  • Islet Amyloid Polypeptide / pharmacology
  • Islet Amyloid Polypeptide / therapeutic use
  • Molecular Sequence Data
  • Osteoblasts / cytology
  • Osteoporosis / drug therapy
  • Rats


  • Disulfides
  • Islet Amyloid Polypeptide
  • Allylglycine