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 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.
Kling
Andreas
A
Neuroscience, Medicinal Chemistry, Abbott GmbH and Co KG, Discovery Research, D-67008, PO Box 210805, Ludwigshafen, Germany
Backfisch
Gisela
G
Delzer
Jürgen
J
Geneste
Hervé
H
Graef
Claudia
C
Hornberger
Wilfried
W
Lange
Udo E W
UE
Lauterbach
Arnulf
A
Seitz
Werner
W
Subkowski
Thomas
T
D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis* / Q000494:pharmacology*; D018938:Caco-2 Cells; D002448:Cell Adhesion / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D019791:Guanidine / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008968:Molecular Conformation; D010920:Placenta / Q000187:drug effects / Q000378:metabolism; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000577:Amides; D001552:Benzazepines; D007202:Indicators and Reagents; D039041:Integrin alpha4beta1; D039302:Integrin alphaVbeta3; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019791:Guanidine