Design and synthesis of 1,5- and 2,5-substituted tetrahydrobenzazepinones as novel potent and selective integrin alphaVbeta3 antagonists

The design and synthesis of novel integrin alpha(V)beta(3) antagonists based on a 1,5- or 2,5-substituted tetrahydrobenzaezpinone core is described. In vitro activity of respective compounds was determined via alpha(V)beta(3) binding assay, and selected derivatives were submitted to further characte...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2003-04, Vol.11 (7), p.1319-1341
Main Authors: Kling, Andreas, Backfisch, Gisela, Delzer, Jürgen, Geneste, Hervé, Graef, Claudia, Hornberger, Wilfried, Lange, Udo E W, Lauterbach, Arnulf, Seitz, Werner, Subkowski, Thomas
Format: Article
Language:English
Subjects:
Amides - chemical synthesis
Amides - pharmacology
Animals
Benzazepines - chemical synthesis
Benzazepines - pharmacology
Caco-2 Cells
Cell Adhesion - drug effects
Crystallography, X-Ray
Drug Design
Enzyme-Linked Immunosorbent Assay
Female
Guanidine - chemistry
Humans
In Vitro Techniques
Indicators and Reagents
Integrin alpha4beta1 - antagonists & inhibitors
Integrin alphaVbeta3 - antagonists & inhibitors
Magnetic Resonance Spectroscopy
Microsomes, Liver - drug effects
Microsomes, Liver - metabolism
Molecular Conformation
Placenta - drug effects
Placenta - metabolism
Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors
Rats
Stereoisomerism
Structure-Activity Relationship
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The design and synthesis of novel integrin alpha(V)beta(3) antagonists based on a 1,5- or 2,5-substituted tetrahydrobenzaezpinone core is described. In vitro activity of respective compounds was determined via alpha(V)beta(3) binding assay, and selected derivatives were submitted to further characterization in functional cellular assays. SAR was obtained by modification of the benzazepinone core, variation of the spacer linking guanidine moiety and core, and modification of the guanidine mimetic. These efforts led to the identification of novel alpha(V)beta(3) inhibitors displaying potency in the subnanomolar range, selectivity versus alpha(IIb)beta(3) and functional efficacy in relevant cellular assays. A method for the preparation of enantiomerically pure derivatives was developed, and respective enantiomers evaluated in vitro. Compounds 31 and 37 were assessed for metabolic stability, resorption in the Caco-2 assay and pharmacokinetics.
ISSN:0968-0896