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Compound 1, (7-methoxy-N-((6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine) is a potent, selective inhibitor of c-Met (mesenchymal-epithelial transition factor), a receptor tyrosine kinase that is often deregulated in cancer. Compound 1 displayed desirable pharmacokinetic properties in multiple preclinical species. Glutathione trapping studies in liver microsomes resulted in the NADPH-dependent formation of a glutathione conjugate. Compound 1 also exhibited very high in vitro NADPH-dependent covalent binding to microsomal proteins. Species differences in covalent binding were observed, with the highest binding in rats, mice, and monkeys (1100-1300 pmol/mg/h), followed by dogs (400 pmol/mg/h) and humans (144 pmol/mg/h). This covalent binding to protein was abolished by coincubation with glutathione. Together, these in vitro data suggest that covalent binding and glutathione conjugation proceed via bioactivation to a chemically reactive intermediate. The cytochrome (CYP) P450 enzymes responsible for this bioactivation were identified as cytochrome P450 3A4, 1A2, and 2D6 in human and cytochrome P450 2A2, 3A1, and 3A2 in rats. The glutathione metabolite was detected in the bile of rats and mice, thus demonstrating bioactivation occurring in vivo. Efforts to elucidate the structure of the glutathione adduct led to the isolation and characterization of the metabolite by NMR and mass spectrometry. The analytical data confirmed conclusively that the glutathione conjugation was on the 4-C position of the isothiazole ring. Such P450-mediated bioactivation of an isothiazole or thiazole group has not been previously reported. We propose a mechanism of bioactivation via sulfur oxidation followed by glutathione attack at the 4-position with subsequent loss of water resulting in the formation of the glutathione conjugate. Efforts to reduce bioactivation without compromising potency and pharmacokinetics were undertaken in order to minimize the potential risk of toxicity. Because of the exemplary pharmacokinetic/pharmacodynamic (PK/PD) properties of the isothiazole group, initial attempts were focused on introducing alternative metabolic soft spots into the molecule. These efforts resulted in the discovery of 7-(2-methoxyethoxy)-N-((6-(3-methyl-5-isothiazolyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine (compound 2), with the major metabolic transformation occurring on the naphthyridine ring alkoxy substituent. However, a glutathione conjugate of compound 2 was produced in vitro and in vivo in a manner similar to that observed for compound 1. Furthermore, the covalent binding was high across species (360, 300, 529, 208, and 98 pmol/mg/h in rats, mice, dogs, monkeys, and humans, respectively), but coincubation with glutathione reduced the extent of covalent binding. The second viable alternative in reducing bioactivation involved replacing the isothiazole ring with bioisosteric heterocycles. Replacement of the isothiazole ring with an isoxazole or a pyrazole reduced the bioactivation while retaining the desirable PK/PD characteristics of compounds 1 and 2.

AMG 458 {1-(2-hydroxy-2-methylpropyl)-N-[5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl]-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide} is a potent, selective inhibitor of c-Met, a receptor tyrosine kinase that is often deregulated in cancer. AMG 458 was observed to bind covalently to liver microsomal proteins from rats and humans in the absence of NADPH. When [(14)C]AMG 458 was incubated with liver microsomes in the presence of glutathione and N-acetyl cysteine, thioether adducts were detected by radiochromatography and LC/MS/MS analysis. These adducts were also formed upon incubation of AMG 458 with glutathione and N-acetyl cysteine in buffers at pH 7.4. In vivo, the thioether adducts were detected in bile and urine of bile duct-cannulated rats dosed with [(14)C]AMG 458. The two adducts were isolated, and their structures were determined by MS/MS and NMR analysis. The identified structures resulted from a thiol displacement reaction to yield a quinoline thioether structure and the corresponding hydroxyaryl moiety. The insights gained from elucidating the mechanism of adduct formation led to the design of AMG 458 analogues that exhibited eliminated or reduced glutathione adduct formation in vitro and in vivo.

A stereoselective synthesis of the hydroxyethylene dipeptide isostere 1 is described. The route employs a substrate-directed kinetic protonation of an alpha/gamma-substituted lactone to afford the desired stereochemistry. A method for converting the diastereomerically enriched intermediate lactone to the ring-open form with retention of stereochemistry is demonstrated. A novel procedure for utilizing N,N-dibromo-5,5-dimethylhydantoin in Hofmann rearrangements is disclosed. This route was used to prepare amino alcohol 1, the core portion of the HIV protease inhibitor A-792611, in 46% yield from phenylalanine-derived epoxide 2.

Oritavancin is a semi-synthetic glycopeptide antibiotic which is structurally related to vancomycin. When oritavancin bisphosphate is dried in vacuo with heat, a new compound forms. This new compound is stable only in the solid state and reverts to oritavancin in solution. Highly enriched samples of this compound were obtained by preparative HPLC and the structure of this compound was elucidated by using one and two-dimensional ( 1 H and 13 C) NMR spectroscopy in conjunction with computer-assisted molecular modeling. It has been determined that oritavancin adopts a conformation similar to that of vancomycin in solution, while the new compound is the unnatural R -AB-biaryl atropisomer of oritavancin. This is the first observation and isolation of an AB-biaryl atropisomer in an intact member of the vancomycin family of glycopeptide antibiotics.

A new reaction of erythronolides, an intramolecular hetero-Diels-Alder, has been discovered. Heated aqueous alcoholic solutions of ABT-773 (1) and its cis isomer (3) convert slowly to cycloadducts 2 and 4, respectively. Optimal reaction conditions, mechanistic studies supported by molecular modeling, and biological activity data are reported. Single-crystal X-ray structures for both adducts 2 and 4 have been obtained.

Cristallisation dans le groupe P2 1 /c avec a=12,169, b=10,860 et c=17,282 A, β=103,11°, Z=4. Affinement jusqu'a R=0,033. Formation d'un dimere de dimeres a l'etat solide comme son analogue cis-diammine platine(II). Augmentation des distances Pt-Pt dans le complexe etudie par rapport a son analogue due a des repulsions steriques entre les coordinats adjacents dans le plan

Les deux complexes de platine(II) presentent une coordination plan carree autour des atomes Pt tandis que le complexe de platine(IV) presente une coordination octaedrique autour de l'atome Pt. Orientation des coordinats hydroxy-2 pyridine dans le premier compose du titre, selon une conformation antirotationnelle

Explication d'apres les resultats de spectroscopie optique polarisee sur monocristal et par analyse par la methode d'onde Xα de la couleur bleue et des interactions Pt-Pt pour le bleu de cis-diamminoplatine α-pyridone; cis [Pt(NH 3 ) 2 (C 5 H 4 NO)] 4 (NO 3 ) 5 •H 2 O

Preparation du dimere [(NO 3 )(NH 3 ) 2 Pt(C 5 H 4 NO) 2 Pt(NH 3 ) 2 (H 2 O)] (NO 3 ) 3 •2H 2 O par oxydation chimique du cis-diammineplatine α-pyridone avec l'acide nitrique. L'isomere tete a queue de [(NO 3 )(NH 3 ) 2 Pt (C 5 H 4 NO) 2 Pt(NH 3 ) 2 (NO 3 )](NO 3 ) 2 •1/2H 2 O est prepare par oxydation avec l'acide nitrique du dimere analogue de platine(II) [(NH 3 ) 2 Pt(C 5 N 4 NO) 2 Pt(NH 3 ) 2 ] (NO 3 ) 2 •2H 2 O. Structure cristalline des deux complexes formes. Etude par voltammetrie differentielle et cyclique