A novel strategy for ADME screening of prodrugs: combined use of serum and hepatocytes to integrate bioactivation and clearance, and predict exposure to both active and prodrug to the systemic circulation.

Common strategies to optimize prodrugs use either in vitro or rodent in vivo approaches, which do not consider elimination pathways that do not result in the generation of the desired product or might be misleading because of species differences, respectively. As a step forward, we have incorporated a novel application of hepatocytes into our prodrug optimization strategy to increase the bioavailability of a poorly soluble drug candidate by attaching a charged ester linker. The model involves the incubation of hepatocytes from multiple species in serum-containing medium to mimic formation as well as simultaneous metabolism of both prodrug and active drug. Using this strategy, a correlation between the in vitro AUC and the AUC after intravenous administration was obtained for active drug formation in several species. Moreover, hepatocytes correctly predicted the likelihood of undesired exposure with nonhydrolyzed prodrug. This novel approach enabled us to identify several prodrugs, which showed improved exposure over a wide dose range. Furthermore, a strategy was developed resulting in a decision tree that can be used to determine the applicability of the hepatocyte model in the screening process.

Fragment-based discovery of hydroxy-indazole-carboxamides as novel small molecule inhibitors of Hsp90.

Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe the identification of novel small molecular weight inhibitors of Hsp90 using a fragment based approach. Fragments were selected by docking, tested in a biochemical assay and the confirmed hits were crystallized. Information gained from X-ray structures of these fragments and other chemotypes was used to drive the fragment evolution process. Optimization of these high µM binders resulted in 3-benzylindazole derivatives with significantly improved affinity and anti-proliferative effects in different human cancer cell lines.

Chlorothiophenecarboxamides as P1 surrogates of inhibitors of blood coagulation factor Xa.

Neutral chlorothiophenecarboxamides bearing an amino acid and a substituted aniline were synthesized and investigated for their factor Xa inhibitory activity in vitro. From selected 2-methylphenyl morpholinones the solution properties were determined. The most soluble and active compounds were then investigated in different animal species to compare the pharmacokinetic parameters. This led to a potent, water soluble and orally bioavailable candidate for further development: EMD 495235.