4-[1-环己基-4-(4-氟苯基)-1H-咪唑-5-基]-2-嘧啶胺盐酸盐

PF-670462 is a potent and selective inhibitor of CKIε and CKIδ, with IC ₅₀ s of 7.7 nM and 14 nM, respectively. PF-670462 shows less than 30-fold selevtivity for EGFR and SAPK2A/p38, with IC ₅₀ s of 150 nM and 190 nM, respectively. PF-670462 also causes a redistribution of the GFP signal to the cytoplasm in a concentration-dependent manner, with an EC ₅₀ of 290 ± 39 nM in CKIε-transfected COS7 cells. PF-670462 is a potent inhibitor of Wnt/β-catenin signaling, with an IC ₅₀ of ∼17 nM. PF-670462 (1 μM) is a weak inhibitor of proliferation, and only modestly suppresses the growth of HEK293 and HT1080 cells. PF-670462 (100 nM) strongly inhibits CK1ε and CK1δ, consistent with its effect on Wnt/β-catenin signaling.

PF-670462 (50 mg/kg, s.c.) produces robust phase delays, and the activity remains persistent, with no discernible correction in the absence of exogenous zeitgebers in rats. PF-670462 (25, 50, and 100 mg/kg, s.c.) induces dose-dependent phase shift. PF-670462 (50 mg/kg; s.c.) significantly phase delays the rhythmic transcription of Bmal1, Per1, Per2 and Nr1d1 in both liver and pancreas by 4.5 ± 1.3 h and 4.5 ± 1.2 h, respectively, 1 day after administration. In the suprachiasmatic nucleus (SCN), the rhythm of Nr1d1 and Dbp mRNA expression is also delayed by 4.2 and 4 h, respectively.