Quantitative Structure - Activity Relationships for Microsomal Enzymatic System Modulants. Part I: Inhibitors

Abstract

The microsomal enzymatic system (MES) occupies, together with immune and antioxidant systems, a key position in the overall immunochemical homeostasis maintenance system [1]. The main biological role of MES consists in the oxidation of low-molecular-weight compounds, including products formed in the living cell (cholesterol, saturated and unsaturated fatty acids, prostaglandins, etc.) and substances coming into the organism from outside (drugs, toxicants, etc.) [2]. As is known, xenobiotics (including drugs) are capable of modifying the activity of MES [3]. Indeed, the induction of MES, on the one hand, stimulates its own metabolism significantly reducing the duration and expression of the pharmacological effect and, on the other hand, influences the biotransformation of other drugs administered simultaneously with such an “inductor.” Any depression of MES leads to increasing toxicity of most xenobiotics and to side effects of the usual drugs (e.g., to those observed upon the joint administration of ketoconazole and terfenadine [4]). If we take into account only the pharmacometabolizing function of the liver, assessment of the ability of compounds to control the MES function would virtually always be “negative” [4, 5]. Nevertheless, such properties may have qualitatively different characteristics. From the standpoint of MES being involved into the immunochemical homeostasis maintenance, the ability of modulating this activity must be considered as a potential means of relieving symptoms and correcting a large number of disorders [6 – 9], especially those affecting the hepatobiliary system. This statement refers to both MES depressants and activators. The metabolism of some xenobiotics proceeds by the pathway of intoxication, leading to the formation of intermediates possessing carcinogenic, mutagenic, and hepatoand/or embryotoxicity. The important role played by the induction of some isoforms of cytochrome P-450 in carcinogenesis and mutagenesis drives the search for new microsomal inhibitors as potential antidotes for procarcinogens (polycyclic aromatics, polychlorinated biphenyls, etc.) and as antitumor drugs [7]. These aspects suggest promising directions in the search for MES modulants and account for the interest of researchers studying quantitative structure – activity relationships (QSAR) for such agents using various method [10 – 13]. We have studied QSAR problems for MES activity inhibitors and inductors using a substructural approach and a SARD computer modeling system [14]. The initial information included structural data and the results of screening based on the hexenal-induced sleep test involving 208 azoles synthesized and studied at the Bashkir State Medical University (Ufa) (see, e.g., [15, 16]). All substances were conditionally divided into three classes: inductors, “indifferent substances” (neutrals), and inhibitors. This classification was based on the criterion of reliable ( p < 0.05) difference in the hexenal sleep duration – the most informative parameter ensuring in vivo evaluation of the degree of P-450b isoform induction [17] – between mice in the control and test groups. Below we report on data concerning the depressant effect of various azole derivatives on MES. The alternative groups in the learning set necessary for the QSAR analysis contained 66 azole derivatives of types I – III, including 34 MES inhibitors (acting as depressants in the hexenal sleep test) and 32 compounds exhibiting no activity in this test: Pharmaceutical Chemistry Journal Vol. 35, No. 6, 2001