Biotransformation of Geldanamycin and 17-Allylamino-17-Demethoxygeldanamycin by Human Liver Microsomes: Reductive versus Oxidative Metabolism and Implications
- W. Lang, G. Caldwell, Jian Li, G. Leo, W. Jones, J. Masucci
- Biology, ChemistryDrug Metabolism And Disposition
- 1 January 2007
The results provide direct evidence for understanding the 17-substituent effects of these benzoquinone ansamycins on their phase I metabolism, reactivity with glutathione, and acute hepatotoxicity.
Allometric scaling of pharmacokinetic parameters in drug discovery: Can human CL, Vss and t1/2 be predicted fromin-vivo rat data?
- G. Caldwell, J. Masucci, Zhengyin Yan, W. Hageman
- BiologyEuropean journal of drug metabolism and…
- 1 April 2004
It is shown, using a large diverse set of drugs, that a fixed exponent allometric scaling approach can be used to predict humanin-vivo PK parameters CL, Vss and t1/2 solely from rat data with acceptable accuracy for making go/no-go decisions in drug discovery.
Dihydroquinone ansamycins: toward resolving the conflict between low in vitro affinity and high cellular potency of geldanamycin derivatives.
The in vivo accumulation of the high-affinity dihydroquinone ansamycins in tumor cells contributes to the antitumor activity of these compounds and alters the understanding of the active species driving the efficacy of this class of compounds.
Evaluation of the immobilized artificial membrane phosphatidylcholine. Drug discovery column for high-performance liquid chromatographic screening of drug-membrane interactions.
The new pre-preclinical paradigm: compound optimization in early and late phase drug discovery.
- G. Caldwell, D. Ritchie, J. Masucci, W. Hageman, Z. Yan
- Biology, ChemistryCurrent Topics in Medicinal Chemistry
- 31 October 2001
To address the problem of attrition rates of NCEs in preclinical and clinical development and drug scale-up issues, pharmaceutical companies need to reorganize their preclinical departments from a traditional linear approach to a parallel approach.
The IC50 Concept Revisited
The most important part of the experimental design is to measure the rate of production of [P] during the linear phase of the time course of the reaction and to prove that the enzyme- catalyzed reaction is reversible.
N-GLUCURONIDATION OF THE PLATELET-DERIVED GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITOR 6,7-(DIMETHOXY-2,4-DIHYDROINDENO[1,2-C]PYRAZOL-3-YL)-(3-FLUORO-PHENYL)-AMINE BY HUMAN…
Results suggested that glucuronidation of JNJ-10198409 in human liver microsomes is catalyzed by multiple UGT1A enzymes, and conjugation at the nitrogens of the pyrazole ring represents a new structural moiety for UGT 1A-mediated reactions.
Inhibitors of Ketohexokinase: Discovery of Pyrimidinopyrimidines with Specific Substitution that Complements the ATP-Binding Site.
- B. Maryanoff, J. O'Neill, I. Petrounia
- Chemistry, BiologyACS Medicinal Chemistry Letters
- 28 April 2011
X-ray cocrystal structures of KHK complexes of 3, 8, and 47 revealed the important interactions within the enzyme's adenosine 5'-triphosphate (ATP)-binding pocket, and potent, selective inhibitors of human hepatic KHK within a series of pyrimidinopyrimidines were identified.
The use of the suicide CYP450 inhibitor ABT for distinguishing absorption and metabolism processes in in-vivo pharmacokinetic screens
It is suggested that this rapid ratin-vivo PK screen where the oxidative drug metabolism has been attenuated using the suicide CYP450 inhibitor aminobenzotriazole (ABT) could be used as an alternative toin vivo cannulation assays because of the ease of preparing and interpreting data.