The (pro)renin receptor ((P)RR) plays a crucial role in the development of cardial and renal end-organ damage. Within an academic setting our group aimed to develop small molecular inhibitors of the (P)RR and therefore named renin/ prorenin receptor blockers (RERBs). In this thesis, the effects of two inhibitors of the (P)RR pathway was investigated: the V-ATPase (vacuolar adenosine triphosphatase) inhibitor bafilomycin and genistein which blocks the translocation of promyelocytic leukemia zinc finger (PLZF) to the nucleus. Bafilomycin reduces cell number in a dose dependent manner, genistein in contrast reduces cell number only in high concentrations. In the context of Wnt signalling bafilomycin represses Wnt3a-induced stimulation of axin2. After our group has performed a high-throughput screen for the identification of novel RERB compounds the microsomal stabilities of 121 compounds and the in vivo half-lives of 22 compounds have been determined. In vivo half-lives and predicted in vivo hepatic clearance were correlated showing r2 values of 0,31 for the rat and 0,27 for the human species.
Our data support that the (P)RR is a promising target for oncological indications. Pharmacokinetic data helped to identify drug candidates for future in vivo proof-of-concept animal experiments. The weak coefficients of determination of in vitro and in vivo pharmacokinetic data question the benefit of using microsomal stability as a tool to select compounds for further testing.
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