title: How to blast osteoblasts? Novel dicarba analogues of amylin-(1-8) to treat osteoporosis.
abstract: 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.
authors.affiliation: The School of Chemical Sciences, University of Auckland, 23 Symonds St, Auckland 1010, New Zealand.
authors.forename: Renata
authors.initials: R
authors.lastname: Kowalczyk
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Brimble
authors.forename: Karen E
authors.initials: KE
authors.lastname: Callon
authors.forename: Maureen
authors.initials: M
authors.lastname: Watson
authors.forename: Jillian
authors.initials: J
authors.lastname: Cornish
mesh_terms: D000501:Allylglycine / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003500:Cyclization; D004220:Disulfides / Q000737:chemistry; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000166:cytology; D010024:Osteoporosis / Q000188:drug therapy; D051381:Rats
chemical_list: D004220:Disulfides; D058228:Islet Amyloid Polypeptide; D000501:Allylglycine