The Experts below are selected from a list of 309 Experts worldwide ranked by ideXlab platform
Gregory D Cuny - One of the best experts on this subject based on the ideXlab platform.
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structure activity relationship study of bone morphogenetic protein bmp signaling inhibitors
Bioorganic & Medicinal Chemistry Letters, 2008Co-Authors: Gregory D Cuny, Chetana Sachidanandan, Donna Y Deng, Kenneth D Bloch, Joydev K Laha, Xuechao Xing, Jifeng Liu, Carol S Lai, Randall T PetersonAbstract:A structure-activity relationship study of dorsomorphin, a previously identified inhibitor of SMAD 1/5/8 phosphorylation by bone morphogenetic protein (BMP) type 1 receptors ALK2, 3, and 6, revealed that increased inhibitory activity could be accomplished by replacing the pendent 4-pyridine ring with 4-quinoline. The activity contributions of various nitrogen atoms in the core pyrazolo[1,5-a]pyrimidine ring were also examined by preparing and evaluating pyrrolo[1,2-a]pyrimidine and pyrazolo[1,5-a]pyridine derivatives. In addition, increased mouse Liver Microsome stability was achieved by replacing the ether substituent on the pendent phenyl ring with piperazine. Finally, an optimized compound 13 (LDN-193189 or DM-3189) demonstrated moderate pharmacokinetic characteristics (e.g., plasma t(1/2)=1.6h) following intraperitoneal administration in mice. These studies provide useful molecular probes for examining the in vivo pharmacology of BMP signaling inhibition.
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structure activity relationship and Liver Microsome stability studies of pyrrole necroptosis inhibitors
Bioorganic & Medicinal Chemistry Letters, 2008Co-Authors: Xin Teng, Heather Keys, Junying Yuan, Alexei Degterev, Gregory D CunyAbstract:Abstract Necroptosis is a regulated caspase-independent cell death pathway resulting in morphology reminiscent of passive non-regulated necrosis. Several diverse structure classes of necroptosis inhibitors have been reported to date, including a series of [1,2,3]thiadiazole benzylamide derivatives. However, initial evaluation of mouse Liver Microsome stability indicated that this series of compounds was rapidly degraded. A structure–activity relationship (SAR) study of the [1,2,3]thiadiazole benzylamide series revealed that increased mouse Liver Microsome stability and increased necroptosis inhibitory activity could be accomplished by replacement of the 4-cyclopropyl-[1,2,3]thiadiazole with a 5-cyano-1-methylpyrrole. In addition, the SAR and the cellular activity profiles, utilizing different cell types and necroptosis-inducing stimuli, of representative [1,2,3]thiadiazole and pyrrole derivatives were very similar suggesting that the two compound series inhibit necroptosis in the same manner.
G R Park - One of the best experts on this subject based on the ideXlab platform.
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the effect of propofol on midazolam metabolism in human Liver Microsome suspension
Anaesthesia, 1997Co-Authors: B P Leung, E Miller, G R ParkAbstract:We have studied the inhibitory effects of propofol on the metabolism of midazolam using human Liver Microsomes. In addition, we also investigated whether the lipid in which propofol is solubilised inhibits the metabolism of midazolam. Only high concentrations of propofol (> 100 mmol), greater than those found in clinical practice, inhibited the metabolism of midazolam. The lipid had no effect on the metabolism of midazolam. This study differs from other laboratory studies looking at the inhibitory effects of propofol. These showed inhibition at concentrations similar to those seen in patients. The reasons for the differences may be explained by the use of different substrates or methodology. Propofol may be an enzyme inhibitor, but this remains to be shown to be important in patients.
Qiuquan Wang - One of the best experts on this subject based on the ideXlab platform.
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Click Chemistry Mediated Eu-Tagging: Activity-Based Specific Quantification and Simultaneous Activity Evaluation of CYP3A4 Using 153Eu Species-Unspecific Isotope Dilution Inductively Coupled Plasma Mass Spectrometry
2014Co-Authors: Yong Liang, Xiaowen Yan, Limin Yang, Bo Zhang, Qiuquan WangAbstract:P450 3A4 (CYP3A4) is one of the most important isoforms in the human cytochrome P450 superfamily. It was used as an example in this proof-of-concept study in order to demonstrate an activity-based labeling and then click chemistry (CC) mediated element-tagging strategy for simultaneously specific quantification and activity measurement of an enzyme using species-unspecific isotope dilution inductively coupled plasma mass spectrometry (SUID ICPMS). A dual functional hexynylated 17α-ethynylestradiol activity-based probe was synthesized for specifically labeling CYP3A4 and then CC-mediated Eu-tagging with an azido-DOTA-Eu complex for CYP3A4 quantification and activity measurement in human Liver Microsome and serum samples using 153Eu SUID ICPMS. The LOD (3σ) of CYP3A4 reached 20.3 fmol when monitoring 151/153Eu ICPMS signals, in addition to the merits of specificity and simultaneous activity measurement achieved. We believe that this activity-based CC-mediated element-tagging strategy will liberate more potential advantages of ICPMS in bioanalysis
Wang Qiuqu - One of the best experts on this subject based on the ideXlab platform.
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Click chemistry mediated Eu-tagging: Activity-based specific quantification and simultaneous activity evaluation of CYP3A4 using 153Eu species-unspecific isotope dilution inductively coupled plasma mass spectrometry
AMER CHEMICAL SOC, 2014Co-Authors: Liang Yong, Bo Zhang, Yan Xiaowen, Li Zhaoxin, Yang Limin, Wang QiuquAbstract:P450 3A4 (CYP3A4) is one of the most important isoforms in the human cytochrome P450 superfamily. It was used as an example in this proof-of-concept study in order to demonstrate an activity-based labeling and then click chemistry (CC) mediated element-tagging strategy for simultaneously specific quantification and activity measurement of an enzyme using species-unspecific isotope dilution inductively coupled plasma mass spectrometry (SUID ICPMS). A dual functional hexynylated 17α-ethynylestradiol activity-based probe was synthesized for specifically labeling CYP3A4 and then CC-mediated Eu-tagging with an azido-DOTA-Eu complex for CYP3A4 quantification and activity measurement in human Liver Microsome and serum samples using 153Eu SUID ICPMS. The LOD (3σ) of CYP3A4 reached 20.3 fmol when monitoring 151/153Eu ICPMS signals, in addition to the merits of specificity and simultaneous activity measurement achieved. We believe that this activity-based CC-mediated element-tagging strategy will liberate more potential advantages of ICPMS in bioanalysis. ? 2014 American Chemical Society
Roger Rahmani - One of the best experts on this subject based on the ideXlab platform.
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use of a human Liver Microsome bank in drug glucuronidation studies
Toxicology in Vitro, 1991Co-Authors: Bruno Lacarelle, J F Rajaonarison, T Gauthier, M Placidi, J Catalin, Roger RahmaniAbstract:Abstract A bank of readily available, well characterized human hepatic microsomal fractions (29 samples from different Livers) has been established. The enzymatic characteristics of each Microsome sample were determined using three specific UDP-glucuronosyltransferase (UDPGT) substrates (p-nitrophenol for UDPGT1, 4-hydroxybiphenyl for UDPGT2A and monodigitoxoside digitoxigenin (DT1) for UDPGT7). After characterization, the bank was used to study the phase II biotransformation processes of two drugs: an antiviral, zidovudine (AZT), and an intermediate metabolite of digoxin, monodigitoxoside digoxigenin (DG1). Results showed a wide interindividual variability for the glucuronidation rate of 4-hydroxybiphenyl, DT1, AZT and DG1. Surprisingly, this variability was lower for p-nitrophenol. No significant correlation was found between the various activities except between DG1 and DT1 UDPGT activities and 4-hydroxybiphenyl and AZT UDPGT activities. For AZT, further experiments showed that glucuronidation of this antiviral compound was inhibited by 4-hydroxybiphenyl and chloramphenicol but not by morphine, p-nitrophenol, acetaminophen, or bilirubin. Finally, the results strongly suggest the respective involvement of UDPGT2A and UDPGT7 in the glucuronidation of AZT and DG1.