Isolation and identification of a major metabolite of PNU-107859, an MMP inhibitor from the biliary fluid of rats.
PNU-107859, an important representative structure in a novel class of matrix metalloproteinases (MMP) inhibitors known as thiadiazoles, was found to be quickly eliminated from rats. A major metabolite (approximately 10% of total dose) was found to be present in the bile of rats. The metabolite in question was isolated and purified from the bile fluids collected from six cannulated rats. From a total of approximately 75 mg of PNU-107859 administered to rats, 3.3 mg of the metabolite was recovered. The NMR and mass spectrometry results indicated that the metabolite is a glucuronide conjugate (1-deoxy-1beta-substituted D-glucopyranosiduronic acid) of the intact drug. Furthermore, the UV, MS, and NMR data established that the conjugate is located at the nitrogen alpha to the thiocarbonyl of the thiadiazole ring.
Discovery Technologies, Structural, Analytical, and Medicinal Chemistry, and Transgenic Therapeutic in Vivo Core Group, Pharmacia and Upjohn, Kalamazoo, Michigan 49001, USA. MTKUO@am.pnu.com
M S
MS
Kuo
D A
DA
Yurek
S A
SA
Mizsak
M D
MD
Prairie
S J
SJ
Mattern
T F
TF
DeKoning
D000818:Animals; D001646:Bile / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013830:Thiadiazoles / Q000378:metabolism*; D014508:Urea / Q000031:analogs & derivatives* / Q000378:metabolism
D061965:Matrix Metalloproteinase Inhibitors; C116568:PNU 107859; D011480:Protease Inhibitors; D013830:Thiadiazoles; D014508:Urea