N-Benzoyl amino acids as ICAM/LFA-1 inhibitors. Part 2: structure-activity relationship of the benzoyl moiety.
o-Bromobenzoyl l-tryptophan 1 inhibits the association of LFA-1 with ICAM-1 with an IC(50) of 1.7microM. Evaluation of the structure-activity relationship of the benzoyl moiety shows that 2,6-di-substitutions greatly enhance potency of this class of inhibitors. Electronegative substitutions that favor a 90 degrees angle between the benzoyl ring and the amide bond yield the most potent compounds. There is a strong correlation between the potency of the compounds and the difference between the ab initio energy at 90 degrees and the global minima energy for given compounds. Combining the favored benzoyl substitutions with l-histidine and l-asparagine resulted in a 15-fold increase in potency over compound 1.
Burdick
Daniel J
DJ
Department of Medicinal Chemistry, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080, USA. burdick.dan@gene.com
Marsters
James C
JC
Aliagas-Martin
Ignacio
I
Stanley
Mark
M
Beresini
Maureen
M
Clark
Kevin
K
McDowell
Robert S
RS
Gadek
Thomas R
TR
D000596:Amino Acids / Q000737:chemistry* / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000596:Amino Acids; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1