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

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 Nα-Fmoc Nε-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.