Pharmacodynamic And Pharmacokinetic Studies Of A New Potential Anti-tumor Angent: CPD7

Aim: As a structural analogue of Afatinib, an anti-tumor new durg, thepharmacodynamics activity and the availability of CPD7would be the key in new drugdevelopment. This thesis focused on the pharmacological activity and pharmacokineticproperties of CPD7to lay the foundation for its further development.Methods: For the cell proliferation inhibition,8kinds of cancer cell lines weretreated with different concentration of CPD7for72hs, and the IC50were calculated byGraphpad Prism5. For the Pharmacokinetics study, rats were treated with CPD7at asingle intravenous (IV) dose and a single oral dose, respectively. The PK data of CPD7were determinated in bile, urine, feces and organ tissues after a single oral dose,respectively. CPD7was incubated in the liver microsomes. The intrinsic clearance ofCPD7was calculated in the liver microsomes from five different species, and the mainmetabolites and metabolic enzymes were identified in HLMs.Results: CPD7could inhibit the proliferation of8cancer cell lines in vitro, and theIC50of CPD7were2.18μM and2.79μM in A549and NCI-H441, respectively. Thepharmacokinetic characteristics of CPD7in rats as follows:1) after a intravenous dose,the average plasma clearance (CL) and half-life (t1/2) were40.8mL min kg-1and5.12h,the average bioavailability (F) are33.2%（1.0mg·kg-1）,41.2%（3.0mg·kg-1）and51.1%（10mg·kg-1）in different oral dose, respectively;2) CPD7could spread quicklyto the organization in rats, including lung, small intestine, stomach, spleen and liver inthe distribution after an oral dose. The cumulative excretion of CPD7were25.4±3.35%，0.191±0.120%and2.22±0.890%in feces, urine and bile at48h post-dose,respectively. The results of incubation in the liver microsomes shows:1) metabolicstability are different in different species, the intrinsic clearances of CPD7are about18.4、22.4、98.2、38.8and11.3μL min-1·mg-1proteins in mouse, rat, dog, monkey andhuman liver microsome respectively, meaning that the metabolic rate are different in theliver microsomes of the five species;2) metabolites were proposed to be produced via N-dealkylation and N-oxidation of CPD7, and CYP3A and FMO were major metabolicenzymes responsible for CPD7metabolism.Conclusion: This thesis examined the pharmacological activity of CPD7andobtained some pharmacokinetics in vitro and rats, which provides a scientific basis anddata support for its further new drug development.