Novel piperidine derivatives: inhibitory properties towards cytochrome P450 isoforms, and cytoprotective and cytotoxic characteristics

Abstract

The ability of a series of eight piperidine derivatives, substituted at positions 1, 3 and 4, to inhibit P450-dependent metabolism of specific substrates, is reported. Five different P450 isoforms (1A1, 1A2, 2B1, 2E1 and 3A1) in differentially induced rat liver microsomes were used for this purpose. From the results it is concluded that compound 2 was the most potent and moreover, highly selective inhibitor for P4502B1 with an IC 50 of 2.5 μM. Compound 3 appeared to have high selectivity for P4501A1 but not for P4501A2 (IC 50s 80 and > 1000 μM, respectively). P4502B1 was found to be the most susceptible P450 isoform for inhibition by compounds 2, 3 and 6, while P4502E1 was largely insensitive to the inhibitory properties of all piperidine derivatives. A preliminary SAR study for the cytotoxicity, cytoprotective and P450 inhibitory properties of the piperidine derivatives, was also attempted. Using freshly isolated rat hepatocytes, the toxicity of the compounds was estimated and expressed as lactate dehydrogenase (LDH) leakage, lipid peroxidation (LPO) levels and GSH depletion. Considering the P450 inhibition and cytotoxicity results, compounds 2 and 3 were tested for possible protective activity against paracetamol-induced cytotoxicities. It was found that compound 2 protects completely against LDH leakage and LPO caused by paracetamol in rat hepatocytes isolated from β-naphthoflavone (β-NF) pretreated rats. It is concluded that the piperidine structures studied proved to be potentially valuable lead compounds for the design of potent and selective P450 inhibitors and for non-toxic cytoprotective agents as well.