Pharmacological evaluation of FK706, a novel and potent elastase inhibitor

• Published in: Japanese Journal of Pharmacology 1997, Vol.73 (suppl.1), p.114-114
• Main Authors: Yamazaki, Akiko, Shinguh, Yasuhiko, Inamura, Noriaki, Nakahara, Kunio, Shirnomura, Kyoujchi, Ono, Takaharu
• Format: Article
• Language: English
• ISSN: 0021-5198; 1347-3506
• DOI: 10.1016/S0021-5198(19)44964-0

We found a novel and potent elastase inhibitor, FK706, sodium 2-[4-[[(S)-1-[[(S)-2-([(RS)-3,3,3-trifluoro-1-isopropyl-2-oxopropyl]aminocarbonyl]pyrrolidin-1-yl]carbonyl-2-methylpropyl]aminocarbonyl]benzoylamino]acetate. Kinetic study demonstrates that FK706 is a slow-binding inhibitor with a Ki value of 4.2 nM. FK706 inhibited elastase activities of human neutrophil, mouse neutrophil, and porcine pancreas measured using synthetic substrate with IC_50 values of 83 nM, 22 nM and 100 nM, respectively. FK706 also inhibited human neutrophil elastase (HNE) activity measured using natural substrate, insoluble elastin, with an IC_50 value of 230 nM. FK706 did not inhibit other serine proteinases such as human pancreatic trypsin, human pancreatic alpha-chymotrypsin, and human leukocyte cathepsin G at the concentration up to 340 μM. FK706 prevented HNE-induced lung hemorrhage in hamsters with an ED_50 value of 2.4 μg/site by intratracheal administration. These results suggest that FK706 would be useful in the treatment of pulmonary inflammatory diseases such as pulmonary emphysema and respiratory distress syndrome which neutrophil elastase is considered to play an important role for the induction of these diseases.