European Molecular Biology Laboratory, Meyerhofstrasse 1,
69012 Heidelberg, Germany,
Departamento de Fisiologia y Farmacologia, Universidad de
Alcala de Henares, 28871, Madrid, Spain,\
and R D Department, Laboratorios Menarini S. A., Alfonso
XII 587, 08912 Badalona, Spain
Mammalian nonpancreatic secretory phospholipase A2 (PLA2) splits the 2-acyl bond in 1,2-diacylphosphatides. This enzyme has been found in high concentrations in the synovial fluid of patients with rheumatoid arthritis, and it has been suggested that inhibitors of this enzyme may have therapeutic value. The three-dimensional structure of human synovial fluid PLA2 (HSF-PLA2) is known both in its native form and in a complex with the transitionstate analogue (TSA) L-1-O-octyl-2-heptylphosphonyl-sn-glycero-3-phosphoethanolamine. The present work is a part of our program to develop PLA2 inhibitors and describes the successful rational modifications introduced into aimed at enhancing its affinity toward HSF-PLA2, based on the combined use of biochemical information, molecular graphics analysis, molecular orbital and molecular mechanics calculations, and the GRID and LUDI programs.
J. Med. Chem. (1994) 37, 337-341.