Figure 10 also shows the main methylation reactions seen in drug metabolism. O-Methylations (Figure 10a) are common reactions of compounds containing a catechol moiety, with a usual regioselectivity for the meta position. The substrates can be xenobiotics and particularly drugs, l-DOPA being a classic example. More frequently, however, O-methylation occurs as a late event in the metabolism of aryl groups, after they have been oxidized to catechols (see Figure 8). This sequence was seen, for example, in the metabolism of the anti-inflammatory drug diclofenac, which in humans yielded 3'-hydroxy-4'-methoxy-diclofenac (23, Figure 11) as a major metabolite with a very long plasma half-life.44 The rates of O-methylation of about 50 substrates in recombinant human soluble COMT has been published and analyzed by partial least squares (PLS) QSAR and 3D-QSAR.45'46 The compounds examined were natural products. The results showed that increased acidity of the catechol group and a larger size of the adjacent substituents strongly decreased the rate of methylation.
S-Methylation of thiol groups (Figure 10a) is documented for such drugs as 6-mercaptopurine (24, Figure 11) and captopril. More recently, it has been shown to be one of the major routes of human metabolism of the vasopeptidase inhibitor omapratilat (25, Figure 11).47 Other substrates are metabolites (mainly thiophenols) resulting from the S-C cleavage of (aromatic) glutathione and cysteine conjugates (see later). Once formed, such methylthio metabolites can be further processed to sulfoxides and sulfones before excretion (see 5.05 Principles of Drug Metabolism 1: Redox Reactions).
Three basic types of N-methylation reaction have been recognized (Figure 10b). A number of primary amines (e.g., amphetamine) have been shown to be in vitro substrates of amine N-methyltransferase. The same is true of some
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