Statin-derived 1,3-oxazinan-2-ones as submicromolar inhibitors of LFA-1/ICAM-1 interaction: stabilization of the metabolically labile vanillyl side chain.
Modification of the vanillyl substituent on a potent, semisynthetic lymphocyte function-associated antigen (LFA)-1/intercellular adhesion molecule (ICAM)-1 binding inhibitor of the statin family resulted in metabolically more stable analogues that displayed submicromolar inhibitory activity in vitro and considerable anti-inflammatory activity in vivo. The benzodioxole derivative 2b emerged with the best overall profile.
Ullrich
Thomas
T
Novartis Institutes for Biomedical Research, A-1235 Vienna, Austria. thomas.ullrich@pharma.novartis.com
Baumann
Karl
K
Welzenbach
Karl
K
Schmutz
Simone
S
Camenisch
Gian
G
Meingassner
Josef G
JG
Weitz-Schmidt
Gabriele
G
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism*; D008148:Lovastatin; D016169:Lymphocyte Function-Associated Antigen-1 / Q000187:drug effects / Q000378:metabolism*; D008862:Microsomes, Liver; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1; D008148:Lovastatin