Structure-based design of novel, urea-containing FKBP12 inhibitors

PS Dragovich, JE Barker, J French…

Index: Dragovich, Peter S.; Barker, John E.; French, Judy; Imbacuan, Michael; Kalish, Vincent J.; Kissinger, Charles R.; Knighton, Daniel R.; Lewis, Cristina T.; Moomaw, Ellen W.; Parge, Hans E.; Pelletier, Laura A. K.; Prins, Thomas J.; Showalter, Richard E.; Tatlock, John H.; Tucker, Kathleen D.; Villafranca, J. Ernest Journal of Medicinal Chemistry, 1996 , vol. 39, # 9 p. 1872 - 1884

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Citation Number: 71

Abstract

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 FKBP12 with inhibition constants (K i, app) approaching 0.10 μM. Analyses of several X-ray crystal structures of FKBP12-urea complexes demonstrate that the urea-containing inhibitors associate with FKBP12 in a manner that is ...