B-90063, a novel endothelin converting enzyme inhibitor isolated from a new marine bacterium, Blastobacter sp. SANK 71894.
A novel endothelin-converting enzyme (ECE) inhibitor, B-90063, was isolated from the culture supernatant of the newly discovered marine bacterium Blastobacter sp. SANK 71894. Based on spectral analyses and chemical reactions, the structure of B-90063 was determined to be bis[6-formyl-4-hydroxy-2-(2'-n-pentyloxazol-4'-yl)-4-pyridon -3-yl]-disulfide (1a). Human and rat ECEs were inhibited more potently by B-90063, with respective IC50 values of 1.0 and 3.2 microM, than were other neutral endopeptidases such as NEP and type-I and -IV collagenases. B-90063 also inhibited the binding of ET-1 to rat ET(A) and bovine ET(B) receptors, though its antagonistic activities were weak. B-90063, thus, may abolish the physiological actions of endothelins through the ECE inhibitory and receptor antagonistic mechanisms.
Takaishi
S
S
Pharmacology and Molecular Biology Research Laboratories, Sankyo Co. Ltd., Tokyo, Japan.
Tuchiya
N
N
Sato
A
A
Negishi
T
T
Takamatsu
Y
Y
Matsushita
Y
Y
Watanabe
T
T
Iijima
Y
Y
Haruyama
H
H
Kinoshita
T
T
Tanaka
M
M
Kodama
K
K
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002417:Cattle; D019332:Endothelin-1 / Q000187:drug effects / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D005285:Fermentation; D006090:Gram-Negative Bacteria / Q000737:chemistry / Q000145:classification / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases; D015394:Molecular Structure; D015260:Neprilysin / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D011728:Pyridones / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D051381:Rats; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D014871:Water Microbiology
C115617:B-90063; D019332:Endothelin-1; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011728:Pyridones; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D013440:Sulfides; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; D000072396:Endothelin-Converting Enzymes