Abstract
Alkyl moieties—open chain or cyclic, linear, or branched—are common in drug molecules. The hydrophobicity of alkyl moieties in drug molecules is modified by metabolic hydroxy functionalization via free-radical intermediates to give primary, secondary, or tertiary alcohols depending on the class of the substrate carbon. The hydroxymethyl groups resulting from the functionalization of methyl groups are mostly oxidized further to carboxyl groups to give carboxy metabolites. As observed from the surveyed cases in this review, hydroxy functionalization leads to loss, attenuation, or retention of pharmacologic activity with respect to the parent drug. On the other hand, carboxy functionalization leads to a loss of activity with the exception of only a few cases in which activity is retained. The exceptions are those groups in which the carboxy functionalization occurs at a position distant from a well-defined primary pharmacophore. Some hydroxy metabolites, which are equiactive with their parent drugs, have been developed into ester prodrugs while carboxy metabolites, which are equiactive to their parent drugs, have been developed into drugs as per se. In this review, we present and discuss the above state of affairs for a variety of drug classes, using selected drug members to show the effect on pharmacologic activity as well as dependence of the metabolic change on drug molecular structure. The review provides a basis for informed predictions of (i) structural features required for metabolic hydroxy and carboxy functionalization of alkyl moieties in existing or planned small drug molecules, and (ii) pharmacologic activity of the metabolites resulting from hydroxy and/or carboxy functionalization of alkyl moieties.
Highlights
Nonpolar alkyl moieties are frequently incorporated into drug molecules to serve pharmacodynamic and/or pharmacokinetic purposes
[6,7,8,9,10].InIndrug drugmolecules moleculescontaining containing more more than than one one class alkyl moiety, as as illustrated in in Figure class of of carbon atoms, the priority of metabolic hydroxylation is dictated by the stability of the intermediate carbon atoms, the priority of metabolic hydroxylation is dictated by the stability of the intermediate free anomalies maymay occur due to prevailing electronic or stericor effects the molecule
Loss of pharmacologic activity has been observed for ibuprofen upon metabolic hydroxylation of the isobutyl group at C1, C2, and C3 (Figure 3)
Summary
Nonpolar alkyl moieties are frequently incorporated into drug molecules to serve pharmacodynamic and/or pharmacokinetic purposes. Alkyl (linear or branched) primary alcohols are further oxidized to Aliphatic Moieties Metabolized by Metabolic. Secondary alcohols (linear or(usually branched)at the farthest class of substrate carbon; primary alcohols are further oxidized to carboxylic acids position from the monosubstituent). Primary alcohols, followed by oxidation to Benzylic methyl aliphatic heterocycles [6,7,8,9,10].InIndrug drugmolecules moleculescontaining containing more more than than one one class alkyl moiety, as as illustrated in in Figure class of of carbon atoms, the priority of metabolic hydroxylation is dictated by the stability of the intermediate carbon atoms, the priority of metabolic hydroxylation is dictated by the stability of the intermediate free anomalies maymay occur due to prevailing electronic or stericor effects the molecule.
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