Cyclic Peptidomimetics as Natriuretic Peptide Clearance Receptor (NPR-C) Antagonists: Series II

摘要

We have recently established that osteocrin (a 133-amino acid bone peptide discovered by Enobia) raises the endogenous levels of CNP by antagonizing NPR-C and restoring normal bone synthesis. CNP and osteocrin bind NPR-C by an almost identical sequence and they cannot be useful drugs for obvious reasons. In series I, we reported on how much smaller linear peptidomimetics can act as osteocrin mimics and effectively block NPR-C. This investigation was aimed at developing cyclic peptidomimetics that would act as NPR-C antagonists and hopefully resolve the PK issues that we encountered with the linear series. We here report on the design, synthesis and in vitro biological testing of stable cyclic NPR-C antagonists.