Strategies for the modulation of phase II metabolism in a series of PKCε inhibitors

Synthesis of 6-Chloro-5-(trifluoroacetyl)pyridine-3-carbonitrile: A Novel, Versatile Intermediate for the Synthesis of Trifluoromethylated Azaindazole Derivatives

“…The incorporation of fluorine into molecules has been the subject of many reviews. 4 Reports of the introduction of fluorine, either directly bound or as a fluoroalkyl group, onto azaindazole heterocycles have appeared; for example, molecules such as B have been reported to be inhibitors of protein kinase C epsilon, 5 and molecules such as C have been reported to be inhibitors of heat-shock proteins HSP90 (Figure 2). 6 Figure 2 Selected bioactive trifluoromethyl pyrazolo [3,4-b]…”

Structure–Metabolism Relationships in the Glucuronidation of d-Amino Acid Oxidase Inhibitors

“…The reduced rate of glucuronidation of 10 was also seen in rat and human microsomes. A recent report exploring strategies for the modulation of phase II metabolism in protein kinase C epsilon (PKCε) inhibitors demonstrated that introduction of proximal polarity to the glucuronidation site is generally effective in attenuating O -glucuronidation while maintaining potency against PKCε . Although speculative, it is conceivable that increased polarity of the hydroxypyridazin-3­(2 H )-one moiety as compared to other α-hydroxycarbonyl-based pharmacophores is at least partially responsible for the slow glucuronidation of 10 .…”