Structure-activity relationship of ortho- and meta-phenol based LFA-1 ICAM inhibitors.
LFA-1 ICAM inhibitors based on ortho- and meta-phenol templates were designed and synthesized by Mitsunobu chemistry. The selection of targets was guided by X-ray co-crystal data, and led to compounds which showed an up to 30-fold increase in potency over reference compound 1 in the LFA-1/ICAM1-Ig assay. The most active compound exploited a new hydrogen bond to the I-domain and exhibited subnanomolar potency.
Lin
Edward Yin-Shiang
EY
Research and Development, Biogen Idec Inc., 14 Cambridge Center, Cambridge, MA 02142, USA. ted.lin@biogenidec.com
Guckian
Kevin M
KM
Silvian
Laura
L
Chin
Donovan
D
Boriack-Sjodin
P Ann
PA
van Vlijmen
Herman
H
Friedman
Jessica E
JE
Scott
Daniel M
DM
D000818:Animals; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D015195:Drug Design; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000187:drug effects*; D008297:Male; D008968:Molecular Conformation; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000737:chemistry
D016169:Lymphocyte Function-Associated Antigen-1; D010636:Phenols; D018799:Intercellular Adhesion Molecule-1; D014443:Tyrosine