Design and synthesis of potent thiol-based inhibitors of endothelin converting enzyme-1.
Through directed screening of compounds prepared as metalloprotease inhibitors a compound, CGS 30084, that had potent endothelin converting enzyme-1 (ECE-1) in vitro inhibitory activity (IC50 = 77 nM) was identified. Herein we report the synthesis and optimization of ECE-1 inhibitory activity of additional analogues from this lead. Compound 3c, the thioacetate methyl ester derivative of compound 4c, was found to be a long acting inhibitor of ECE-1 activity in rats after oral administration.
Fink
C A
CA
Metabolic and Cardiovascular Diseases, Novartis Institute for Biomedical Research, Summit, NJ 07901, USA. cynthia.fink@pharma.novartis.com
Moskal
M
M
Firooznia
F
F
Hoyer
D
D
Symonsbergen
D
D
Wei
D
D
Qiao
Y
Y
Savage
P
P
Beil
M E
ME
Trapani
A J
AJ
Jeng
A Y
AY
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D015195:Drug Design; D000072396:Endothelin-Converting Enzymes; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology
D011480:Protease Inhibitors; D013438:Sulfhydryl Compounds; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes