Fluoro ketone inhibitors of hydrolytic enzymes.
The use of fluoro ketones as inhibitors of hydrolytic enzymes has been investigated. The acetylcholine analogues 6,6-dimethyl-1,1,1-trifluoro-2-heptanone and 3,3-difluoro-6,6-dimethyl-2-heptanone are inhibitors of acetylcholinesterase with Ki values of 16 X 10(-9) M and 1.6 X 10(-9) M, respectively. These fluoro ketones are 10(4)-10(5) times better as inhibitors than the corresponding methyl ketone. Since nucleophiles readily add to fluoro ketones, it is likely that these compounds inhibit acetylcholinesterase by formation of a stable hemiketal with the active-site serine residue. Fluoro ketone substrate analogues are also inhibitors of zinc metallo- and aspartylproteases. 2-Benzyl-4-oxo-5,5,5-trifluoropentanoic acid is an inhibitor of carboxypeptidase A (Ki = 2 X 10(-7) M). Trifluoromethyl ketone dipeptide analogues are good inhibitors of angiotensin converting enzyme. An analogue of pepstatin that contains a difluorostatone residue in place of statine has been prepared and found to be an extremely potent inhibitor of pepsin (Ki = 6 X 10(-11) M). The hydrated ketones are probably the inhibitory species since they are structural mimics of the tetrahedral intermediate that forms during the hydrolysis of peptide substrates.
Gelb
M H
MH
Svaren
J P
JP
Abeles
R H
RH
D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors; D043422:Carboxypeptidases A; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004593:Electrophorus; D005461:Fluorine / Q000494:pharmacology*; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D007659:Ketones / Q000494:pharmacology*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D010434:Pepsin A / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000806:Angiotensin-Converting Enzyme Inhibitors; D002800:Cholinesterase Inhibitors; D007659:Ketones; D011480:Protease Inhibitors; D005461:Fluorine; D006867:Hydrolases; D002268:Carboxypeptidases; D043422:Carboxypeptidases A; D010434:Pepsin A