STRUCTURE-BASED DESIGN OF NOVEL, UREA-CONTAINING FKBP12 INHIBITORS

The structure-based design and subsequent chemical synthesis of novel, urea-containing FKBP12 inhibitors are described. These compounds are shown to disrupt the cis-trans peptidylprolyl isomerase activity of FK BP12 with inhibition constants (K-i,K-app) approaching 0.10 mu M. Anal yses of several X-ray crystal structures of FKBP12-urea complexes demo nstrate that the urea-containing inhibitors associate with FKBP12 in a manner that is similar to, but significantly different from, that obs erved for the natural product FK506.