Structure–activity relationship of ortho- and meta-phenol based LFA-1 ICAM inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 19; pp. 5245 - 5248
• Main Authors: Lin, Edward Yin-Shiang, Guckian, Kevin M., Silvian, Laura, Chin, Donovan, Ann Boriack-Sjodin, P., van Vlijmen, Herman, Friedman, Jessica E., Scott, Daniel M.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.10.2008; Elsevier
• Subjects: Animals; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Combinatorial Chemistry Techniques; Crystallography, X-Ray; Drug Design; ICAM; Immunomodulators; Intercellular Adhesion Molecule-1 - drug effects; LFA-1; LFA-1/ICAM inhibitors; Lymphocyte Function-Associated Antigen-1 - drug effects; Male; Medical sciences; Molecular Conformation; Pharmacology. Drug treatments; Phenols - chemical synthesis; Phenols - chemistry; Phenols - pharmacology; Rats; Stereoisomerism; Structure-Activity Relationship; Tyrosine - chemistry; LFA-1; LFA-1/ICAM inhibitors; ICAM; Cyclohexane derivatives; Rat; Molecular structure; Lymphocyte function associated antigen 1; Morpholine derivatives; Organic sulfide; Structure activity relation; Chemical synthesis; Intercellular adhesion molecule 1; Rodentia; Cell adhesion molecule; Oral administration; Adhesion; X ray diffraction; Vertebrata; Mammalia; Animal; Cinnamic acid derivatives; Carboxamide; Inhibitor; Fluorine Organic compounds; β2 integrin; Pharmacokinetics; Crystalline structure
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.08.062

X-ray co-crystal data assisted the design of LFA-1 ICAM inhibitors based on ortho- and meta-phenol templates, leading to a compound which exploited a new hydrogen bond to the I-domain and which exhibited subnanomolar potency in the LFA-1/ICAM1-Ig assay. 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.