A series of aza-5[H]-phenanthridin-6-ones were synthesized and evaluated as inhibitors of poly ADP-ribose polymerase-1 (PARP-1). Inhibitory potency of the unsubstituted aza-5[H]-phenanthridin-6-ones (i.e., benzonaphthyridones) was dependent on the position of the nitrogen atom within the core structure. The A ring nitrogen analogues (7-, 8-, and 10-aza-5[H]-phenanthridin-6-ones) were an order of magnitude less potent than C ring nitrogen analogues (1-, 2-, 3-, and 4-aza-5[H]-phenanthridin-6-ones). Preliminary stroke results from 1- and 2-aza-5[H]-phenanthridin-6-one prompted structure-activity relationships to be established for several 2- and 3-substituted 1-aza-5[H]-phenanthridin-6-ones. The 2-substituted 1-aza-5[H]-phenanthridin-6-ones were designed to improve the solubility and pharmacokinetic profiles for this series of PARP-1 inhibitors. Most importantly, three compounds from this series demonstrated statistically significant protective effects in rat models of stroke and heart ischemia.
]brivanib alaninate to intact rats, bile duct-cannulated (BDC) rats, intact monkeys, BDC monkeys, and humans. Fecal excretion was the primary route of elimination of drug-derived radioactivity in animals and humans. In BDC rats and monkeys, the majority of radioactivity was excreted in bile. Brivanib alaninate was rapidly and completely converted via hydrolysis to brivanib in vivo. The area under the curve from zero to infinity of brivanib accounted for 14.2 to 54.3% of circulating radioactivity in plasma in animals and humans, suggesting that metabolites contributed significantly to the total drug-related radioactivity. In plasma from animals and humans, brivanib was a prominent circulating component. All the metabolites that humans were exposed to were also present in toxicological species. On the basis of metabolite exposure and activity against VEGF and FGF receptors of the prominent human circulating metabolites, only brivanib is expected to contribute to the pharmacological effects in humans. Unchanged brivanib was not detected in urine or bile samples, suggesting that metabolic clearance was the primary route of elimination. The primary metabolic pathways were oxidative and conjugative metabolism of brivanib.
ABSTRACT:The disposition of stavudine, a potent and orally active nucleoside reverse transcriptase inhibitor, was investigated in six healthy human subjects.
Radiolabelled drug lead candidate leukocyte function-associated antigen 1 antagonist [14 C]spyrocyclic hydantoin: 3,7-triazaspiro[4.4]nonan-7-yl)methyl)thiophene-3-carboxylic acid, 12, was conveniently prepared in three radiochemical steps from (5S,9R)-tert-butyl 9-(4-bromophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-carboxylate 9. The radiochemical yield of 12 was 28.5% from the resolved bromide 9. The preparation of the racemic spyrocyclic hydantoin 3 was obtained via a [312]dipolar cycloaddition reaction between 2 and N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine. The introduction of [ 14 C] cyanide was completed via a palladium (0) catalyzed reaction by the addition of Zn( 14 CN) 2 to aryl bromide 9. The radiochemical and chiral purities of 12 determined by high-performance liquid chromatography were 98.7 and 99.7%, respectively. The specific activity of 12 was 87.5 lCi/mg (48.6 mCi/mmol).
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