Validating the 1,2-Difluoro Motif As a Hybrid Bioisostere of CF3 and Et Using Matrix Metalloproteinases As Structural Probes

Matrix metalloproteinases (MMPs) are involved in a spectrum of physiological processes, rendering them attractive targets for small-molecule drug discovery. Strategies to achieve selective inhibition continue to be intensively pursued, facilitated by advances in structural biology. Herein, we harnes...

Full description

Saved in:
Bibliographic Details
Published inJournal of medicinal chemistry Vol. 63; no. 11; pp. 6225 - 6237
Main Authors Erdeljac, Nathalie, Thiehoff, Christian, Jumde, Ravindra P., Daniliuc, Constantin G., Hoeppner, Sandra, Faust, Andreas, Hirsch, Anna K. H., Gilmour, Ryan
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 11.06.2020
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
FLUORINE
PRODUCT
INHIBITORS
Online AccessGet full text

Cover

More Information
Summary:Matrix metalloproteinases (MMPs) are involved in a spectrum of physiological processes, rendering them attractive targets for small-molecule drug discovery. Strategies to achieve selective inhibition continue to be intensively pursued, facilitated by advances in structural biology. Herein, we harness MMPs 2, 8, 9, and 13 to validate the vicinal difluoro motif as a hybrid bioisostere of CF3 and Et (BITE) in a series of modified barbiturate inhibitors. Crystallographic analyses of representative structures reveal conformations of the vicinal difluoro motif that manifest stabilizing hyperconjugative interactions consistent with the stereoelectronic gauche effect. Detailed docking studies of a potent difluorinated probe with MMP-9 are also disclosed and indicate that the structural basis of inhibition is a consequence of the anisotropic nature of the motif. Significant selectivity of MMP 13 versus MMP-2 can be achieved by subtle chain contraction in a BITE-modified inhibitor.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.0c00648