Pharmacokinetics and in vivo efficacy of a Novel HDAC inhibitor

【摘要】：正In our previous work,we reported a click-chemistry based approach to the synthesis of a novel class of histone deacetylase(HDAC) inhibitors,a promising HDAC inhibitor NSC746457 was identified.This lead compound showed comparable in vitro potency to suberoylanilide hydroxamic acid(SAHA),the launched HDAC inhibitor drug in 2006.Lead optimization of NSC746457 was preformed by using the HDAC2-TSA crystal structure,which led to identification of more potent HDAC inhibitor:isopropyl derivative with an IC50 value of 22 nM.This compound has a chiral center,both R and S configuration were prepared and evaluated in enzyme and cell-based assays.Among them,R configuration(NK-1) has a better activity with an IC50 value of 7 nM and the GI50 values in MTS assay mainly ranging from 100 nM to 500 nM.Primary efficacy in vivo also showed nice activity.Herein,we decided to evaluate its pharmacokinetics and further efficacy in vivo.The bioavailability and pharmacokinetic parameters were achieved through intravenous and oral administration of NK-1 to mice.Dosage regimens will be determined according to its pharmacokinetic property and results of succedent acute toxicity test.and then, we will evaluate its oral activity in comparison with SAHA.