Biochem/physiol Actions

PF-06815345 is a liver-targeted, orally available prodrug, which is converted by liver carboxyesterase (CES1) to its zwitterionic active drug (liver active drug = 33.9 μg/mL in mice 0.5 hr post 300 mg/kg p.o. and 9.0 μg/mL in monkeys 0.5 hr post 30 mg/kg p.o.) that selectively inhibits PCSK9 protein synthesis (IC₅₀ = 3.7 μM by in vitro hPCSK9 translation; 4.95/3.81/21/24/>27-fold selective over CDH1/HSD17B11/PCBP2/RPL27/BCAP31). PF-06815345 effectively lowers plasma PCSK9 in humanized PCSK9 mice (by 26/42/53% 5 hrs post 100/300/500 mg/kg p.o.) and is well tolerated in rats and monkeys in vivo. Note: PF-06815345 is not active in non-humanized mice.

Legal Information

Sold for research purposes under agreement from Pfizer Inc.