1,4-Diazepane-2-ones as novel inhibitors of LFA-1.
The design, synthesis, and biological evaluation of 1,4-diazepane-2-ones as novel LFA-1 antagonists from a scaffold-based combinatorial library are described. Initial optimization of the library lead has resulted in high-affinity antagonists of the LFA-1/ICAM-1 interaction, such as compounds 18d and 18e with IC(50) values of 110 and 70 nM, respectively.
Wattanasin
Sompong
S
Novartis Institute for Biomedical Research, Novartis Pharmaceuticals Corporation, 556 Morris Avenue, Summit, NJ 07901, USA. sompong.wattanasin@pharma.novartis.com
Albert
Rainer
R
Ehrhardt
Claus
C
Roche
Didier
D
Sabio
Michael
M
Hommel
Ulrich
U
Welzenbach
Karl
K
Weitz-Schmidt
Gabriele
G
D002474:Cell-Free System; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D015195:Drug Design; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000187:drug effects*; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
D006573:Heterocyclic Compounds, 1-Ring; D007202:Indicators and Reagents; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1