No abstract

ABSTRACT:Imatinib mesylate (GLEEVEC, GLIVEC, formerly STI571) has demonstrated unprecedented efficacy as first-line therapy for treatment for all phases of chronic myelogenous leukemia and metastatic and unresectable malignant gastrointestinal stromal tumors. Disposition and biotransformation of imatinib were studied in four male healthy volunteers after a single oral dose of 239 mg of 14 C-labeled imatinib mesylate. Biological fluids were analyzed for total radioactivity, imatinib, and its main metabolite CGP74588. Metabolite patterns were determined by radio-high-performance liquid chromatography with off-line microplate solid scintillation counting and characterized by liquid chromatography-mass spectrometry. Imatinib treatment was well tolerated without serious adverse events. Absorption was rapid (t max 1-2 h) and complete with imatinib as the major radioactive compound in plasma. Maximum plasma concentrations were 0.921 ؎ 0.095 g/ml (mean ؎ S.D., n ‫؍‬ 4) for imatinib and 0.115 ؎ 0.026 g/ml for the pharmacologically active N-desmethyl metabolite (CGP74588). Mean plasma terminal elimination half-lives were 13.5 ؎ 0.9 h for imatinib, 20.6 ؎ 1.7 h for CGP74588, and 57.3 ؎ 12.5 h for 14 C radioactivity. Imatinib was predominantly cleared through oxidative metabolism. Approximately 65 and 9% of total systemic exposure [AUC 0-24 h (area under the concentration time curve) of radioactivity] corresponded to imatinib and CGP74588, respectively. The remaining proportion corresponded mainly to oxidized derivatives of imatinib and CGP74588. Imatinib and its metabolites were excreted predominantly via the biliary-fecal route. Excretion of radioactivity was slow with a mean radiocarbon recovery of 80% within 7 days (67% in feces, 13% in urine). Approximately 28 and 13% of the dose in the excreta corresponded to imatinib and CGP74588, respectively.

A "quasi-atomistic receptor model" refers to a three-dimensional receptor surface, populated with atomistic properties (hydrogen bonds, salt bridges, hydrophobic particles, and solvent) mapped onto it. In contrast to other 3D-QSAR approaches, an algorithm developed at our laboratory allows for the adaptation of the receptor-surface defining envelope to the topology of the individual ligand molecules. In addition, it includes H-bond flip-flop particles which can simultaneously act as H-bond donors and H-bond acceptors toward different ligand molecules, binding to the surrogate within a pharmacophore hypothesis. Such particles mimic aminoacid residues able to engage in differently directed H-bonds at the true biological receptor. Ligand-receptor interaction energies are evaluated using a directional force field for hydrogen bonds and salt bridges. On the basis of a series of ligand molecules with individually adapted receptor envelopes, the software Quasar allows a family of receptor models to be generated using a genetic algorithm combined with cross-validation. Our concept has been used to derive semiquantitative structure-activity relationships for the β2-adrenergic, aryl hydrocarbon, cannabinoid, neurokinin-1, and sweet-taste receptor as well as for the enzyme carbonic anhydrase. The receptor surrogates for these systems are able to predict free energies of ligand binding for independent sets of test ligand molecules within 0.4-0.8 kcal/mol (RMS) of the experimental value.

planar conformation required for oxidation is hindered by non-bonding interactions between the propyl groups and the hydrogen atoms in the 2,7,12,17-positions. The favored hydrogenation of 6 with formation of 5 instead of the expected 7 is probably due to hitherto unexplained kinetic factors, since it is almost certain from the acid-catalyzed tautomerization of 5 to 7 that 7 is the thermodynamically more stable tautomer. , 0. Ermer, ibid. 99 (1987) 909 and 26 (1987) 928. Pyrrolophanes with oppositely disposed pyrrole rings are thus far known only in the form of [2.2](2,5)pyrrolophane and some of its derivatives; see the review by W. W. Paudler, M. D. Bezoari in P. M. Keehn, S. M. Rosenfeld: The furan analogue of 2 is present in the crystal as a planar molecule; E. Vogel, M. Sicken, P. Rohrig, H. Schmickler, J. Lex, 0. Ermer, Angew. Chem. 100 (1988) 450; Angew. Chem. I n / . Ed. Engl. 27 (1988) 411. E. Vogel, M. Kocher, J. Lex, 0. Ermer, Isr. J. Chem. 29 (1989) 257 (David-Ginsburg-Memorial Issue).Comparably short hydrogen bonds between N atoms have, to our knowledge. thus Tar only been observed in "proton sponges" in protonated form, see H. A.

No abstract