Novel N-(2-sulfonylamino-5-trifluoromethyl-3-pyridyl)carboxamide derivatives have been prepared and evaluated as phospholipase A2 (PLA2) inhibitors. Among these compounds, IS-741 (sodium salt of 1j), which showed the highest and the most stable therapeutic effect on acute hemorrhagic pancreatitis induced by the closed duodenal loop method in rats, was selected as a candidate for further development.

A novel synthetic drug, IS-741, inhibited cell adhesion in vitro and neutrophil in vivo. Thus, IS-741 inhibited the magnification of pancreatic lesion as well as progression to multiple organ failure in acute pancreatitis models. Furthermore, IS-741 at identical plasma concentrations equally improved the survival rates in animals of various species with severe acute pancreatitis. Based on these observations, it was considered that IS-741 inhibited tissue destruction by neutrophil after inhibiting neutrophil infiltration into the pancreas or other important organs in acute pancreatitis. It was also considered that IS-741 demonstrated various anti-acute pancreatitis effects by interrupting a vicious cycle of inflammation. Therefore, IS-741 is expected to become a useful drug for treating acute pancreatitis and multiple organ failure in clinical settings.

The effect of IS-741 (N-[(2-ethylsulfonylamino)-5-trifluoromethyl-3-pyridyl] cyclohexanecarboxamide monohydrate) on a model for pancreatitis has been previously reported. Recent patho-histological observations of remedial tests using rats found that the IS-741 administered group showed a low degree of tissue infiltration by inflammatory cells (polymorphonuclear leukocytes). We therefore examined cell adhesion, which is the first step in tissue infiltration by activated neutrophils, and investigated the effect of IS-741 on cell adhesion between human umbilical vein endothelial cells (HUVEC) and human promyelo-leukemia cell line (HL-60) cells during lipopolysaccharide stimulation in vitro. IS-741 significantly inhibited the adhesion of HL-60 cells to HUVEC. Further investigation of IS-741 on individual cells revealed that IS-741 mainly affected HL-60 cells. Investigation of the inhibitory effect of IS-741 at the molecular level (targeting adhesion molecules) also revealed that IS-741 had no effect on the appearance of endothelial leukocyte adhesion molecule-1 (ELAM-1), intercellular adhesion molecule-1 (ICAM-1) or vascular cell adhesion molecule-1 (VCAM-1) on HUVEC, which supports the theory that IS-741 is mainly effective on HL-60 cells, even at the molecular level. However, the inhibition of adhesion was noticed in experiments in which an anti-ICAM-1 or anti-VCAM-1 antibody was added to the adhesion test system. Therefore, IS-741 is likely to affect adhesion molecules which belong to the beta1 or beta2 integrin family.

Synthesis and Stereochemistry of I ,2,3,4-Tetra hydro-6-methoxy-2-rnethyl-'I -p&enylisoquinoline and Related Compounds.