Characterization a New Chymotrypsin Inhibitor, FK-448 and Effect of the Inhibitor on Intestinal Absorption of Insulin

Abstract

FK-448, 4-(4-isopropylpiperadinocarbonyl) phenyl 1, 2, 3, 4-tetrahydro-l-naphthoate methanesulfonate was prepared and its inhibitory effect on chymotrypsin, trypsin, thrombin, plasmin, pancreatic kallikrein, plasma kallikrein and cathepsins A, B, C, G and H were examined. Among the various enzymes tested, chymotrypsin was strongly inhibited by FK-448 (IC₅₀: 7.1 X 10^-7M).
We also examined the effect of FK-448 on the intestinal absorption of insulin in the rat. When insulin and FK-448 were administered into the lumen of intestine, the decrease of blood glucose level was observed. In vitro, insulin was degradated by pancreatic enzyme or homogenates of intestine or liver. FK-448 supressed the decrease of insulin activity by pancreatin and its enhancement of intestinal absorption of insulin was found to be related to its inhibition of digestive enzymes, especially, chymotrypsin. Its effect in increasing intestinal absorption of insulin was enhanced by citric acid: the percentage absorptions of insulin from the intestine were 0.72% with 2.5 mg (63u) /kg of insulin with 20 mg/kg of FK-448, and and 1.47% with those doses of insulin and FK-448 in combination with 15 mg/kg of citric acid.