Journal of medicinal chemistry
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Inhibitors of cyclin-dependent kinases (CDK) such as CDK2/cyclin A-E are currently undergoing clinical trials to verify their potential as new anticancer agents. In a previous article we described the lead discovery process of a 3-aminopyrazole class of CDK2/cyclin A-E inhibitors. The endpoint of this process was PNU-292137, a compound endowed with in vivo antitumor activity in a mouse tumor xenograft model. ⋯ Solubility was improved more than 10 times over the starting lead, while plasma protein binding was decreased from 99% to 74%. With exploitation of this globally enhanced in vitro profile, 13 was more active than PNU-292137 in vivo in the A2780 xenograft model showing a tumor growth inhibition of 70%. Proof of mechanism of action was obtained in vivo by immunohistochemical analysis of tumor slices of 13-treated vs untreated animals.
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A series of new 1,2-diphenylimidazole derivatives (1a-x) were synthesized and evaluated for their ability to potentiate gamma-aminobutyric acid (GABA)-evoked currents in Xenopus laevis oocytes expressing recombinant human GABA(A) receptors. Many of these compounds enhanced GABA action with potencies (EC(50) = 0.19-19 muM) and efficacies (maximal efficacies of up to 640%) similar to or greater than those of anesthetics such as etomidate, propofol, and alphaxalone. ⋯ These compounds potentiated the [(3)H]GABA binding to rat brain membranes, suggesting a site of interaction different from that of GABA. As for etomidate, mutation of asparagine-265 in the beta2 subunit of the GABA(A) receptor into serine reduced the ability of derivative 1i to modulate the GABA function.