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

P S Dragovich; J E Barker; J French; M Imbacuan; V J Kalish; C R Kissinger; D R Knighton; C T Lewis; E W Moomaw; H E Parge; L A Pelletier; T J Prins; R E Showalter; J H Tatlock; K D Tucker; J E Villafranca

doi:10.1021/jm950798a

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

J Med Chem. 1996 Apr 26;39(9):1872-84. doi: 10.1021/jm950798a.

Authors

P S Dragovich¹, J E Barker, J French, M Imbacuan, V J Kalish, C R Kissinger, D R Knighton, C T Lewis, E W Moomaw, H E Parge, L A Pelletier, T J Prins, R E Showalter, J H Tatlock, K D Tucker, J E Villafranca

Affiliation

¹ Agouron Pharmaceuticals, Inc., San Diego, California 92121, USA.

PMID: 8627611
DOI: 10.1021/jm950798a

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 (Ki,app) approaching 0.10 microM. 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 similar to, but significantly different from, that observed for the natural product FK506.

MeSH terms

Amino Acid Isomerases / antagonists & inhibitors
Amino Acid Sequence
Carrier Proteins / antagonists & inhibitors*
Carrier Proteins / chemistry
Crystallography, X-Ray
DNA-Binding Proteins / antagonists & inhibitors*
DNA-Binding Proteins / chemistry
Drug Design*
Heat-Shock Proteins / antagonists & inhibitors*
Heat-Shock Proteins / chemistry
Humans
Magnetic Resonance Spectroscopy
Molecular Sequence Data
Peptidylprolyl Isomerase
Structure-Activity Relationship
Tacrolimus / chemistry
Tacrolimus Binding Proteins
Urea / analysis*

Substances

Carrier Proteins
DNA-Binding Proteins
Heat-Shock Proteins
Urea
Amino Acid Isomerases
Tacrolimus Binding Proteins
Peptidylprolyl Isomerase
Tacrolimus