Importance of amine pKa and distribution coefficient in the metabolism of fluorinated propranolol derivatives. Preparation, identification of metabolite regioisomers, and metabolism by CYP2D6.
A series of 1"-mono-, di-, and trifluorinated analogs of propranolol and related steric congeners was prepared, and their metabolism was examined in recombinant-expressed CYP2D6. The structural changes in this series of compounds, principally added fluorines and methyl groups in the 1"-position of the N-isopropyl group, provided compounds that varied in pK(a) by more than 5 log units and also varied in lipophilicity and in steric size. Products of both aromatic hydroxylation and N-dealkylation were observed in the metabolic experiments. The regiochemistry of aromatic hydroxylation at the 4'- and 5'-positions was assigned based on high-pressure liquid chromatography, fluorescence, and mass spectral characteristics of the products and standards. Correlations of the metabolic kinetic parameters K(m) and catalytic efficiency (k(cat)/K(m)) with substituent parameters of the added groups showed that increased basicity (higher pK(a) values) was associated with increased enzyme affinity (low K(m) values) and increased catalytic efficiency. More basic methyl-substituted compounds showed higher affinities for CYP2D6 than the structurally analogous less basic fluorinated congeners, indicating the decrease in affinity of the fluorinated compounds was not due to the size of the N-alkyl substituent. Correlations with log D reflected the degree of ionization and showed that the less lipophilic substrates (more basic compounds) had higher affinity for CYP2D6. These results are consistent with the proposal in the literature that ion pairing of the protonated amine of the substrate with Asp301 in the active site of CYP2D6 is very important to substrate affinity.
Upthagrove
A L
AL
Department of Medicinal Chemistry, University of Washington, Seattle, 98195-7610, USA.
Nelson
W L
WL
D000319:Adrenergic beta-Antagonists / Q000737:chemistry / Q000378:metabolism*; D000588:Amines / Q000737:chemistry / Q000378:metabolism*; D016367:Baculoviridae / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D017611:Fluorine Compounds / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007536:Isomerism; D011433:Propranolol / Q000031:analogs & derivatives / Q000378:metabolism*
D000319:Adrenergic beta-Antagonists; D000588:Amines; D017611:Fluorine Compounds; D011433:Propranolol; D019389:Cytochrome P-450 CYP2D6