Discovery and biological activity of orally active peptidyl trifluoromethyl ketone inhibitors of human neutrophil elastase

Journal of Medicinal Chemistry
P D EdwardsM Zottola

Abstract

Previously we had shown that tripeptidyl trifluoromethyl ketones (TFMKs) possessing an N-terminal diarylacylsulfonamide, such as ICI 200,880 and ICI 200,355, displayed unparalleled protection against the lung damage induced by human neutrophil elastase (HNE) when the inhibitors were administered intratracheally. Since the diarylacylsulfonamides were designed specifically to afford a long residence time in the lung, it was not unexpected that inhibitors from this class of TFMKs were not active when administered orally. Upon evaluating a large number of peptidyl TFMKs possessing a variety of N-terminal groups, several compounds were identified which demonstrated oral activity. Compounds were evaluated for their oral activity by measuring their ability to inhibit the increase in lung weight relative to body weight (Lw/Bw), the increase in red blood cells, and the increase in white blood cells induced by intratracheally administered HNE (100 micrograms/hamster). A number of tripeptidyl trifluoromethyl ketones containing neutral N-terminal groups displayed good oral activity, while those containing basic, acidic, or polar groups did not. Compound 50, possessing an N-terminal 4-(CH3O)C6H4CO group, was particularly effective, reducing...Continue Reading

References

Sep 1, 1991·The American Review of Respiratory Disease·J A Nadel
Oct 1, 1991·The American Review of Respiratory Disease·J C WilliamsR D Krell
Feb 7, 1991·European Journal of Pharmacology·C P SommerhoffJ A Nadel
Jul 1, 1995·Clinical Pharmacokinetics·G A RongenT Thien
Jan 20, 1995·Journal of Medicinal Chemistry·J P BurkhartP W Shum
Mar 1, 1994·Medicinal Research Reviews·P D Edwards, P R Bernstein
Mar 19, 1993·Journal of Medicinal Chemistry·W K HagmannW B Knight

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Citations

Nov 8, 2003·Bioorganic & Medicinal Chemistry·Craig E WheelockBruce D Hammock
Oct 3, 2002·American Journal of Respiratory and Critical Care Medicine·Joanne L WrightAndrew Churg
Jun 27, 2002·Expert Opinion on Investigational Drugs·Hiroyuki Ohbayashi
Jul 17, 1998·Transplantation·Y YamaguchiM Ogawa
Aug 27, 2005·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Kyle Northcote CowanMarlene Rabinovitch
Apr 15, 2017·Science·Chao LiPhil S Baran
Apr 26, 2003·American Journal of Physiology. Heart and Circulatory Physiology·Carlos F SantosAndrew S Greene
Jul 9, 1999·Archives of Biochemistry and Biophysics·M WieczorekJ C Cheronis
Feb 12, 2000·Journal of Medicinal Chemistry·D LeungD P Fairlie
Dec 3, 2002·Journal of Medicinal Chemistry·Craig E WheelockBruce D Hammock
Jan 8, 2015·Journal of Medicinal Chemistry·Arun K Ghosh, Margherita Brindisi
May 23, 2020·The Journal of Organic Chemistry·Xingguo JiangKálmán J Szabó
Jan 11, 2001·Journal of Medicinal Chemistry·K OhmotoM Wieczorek
Nov 5, 1997·Journal of Medicinal Chemistry·C A VealeS Woolson
Jul 19, 2011·Bioorganic & Medicinal Chemistry Letters·Katerina OtrubovaDale L Boger

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