Importance of amine pKa and distribution coefficient in the metabolism of fluorinated propranolol analogs: metabolism by CYP1A2.
A series of 1"-mono-, di-, and trifluorinated analogs of propranolol and related steric congeners was prepared, and their metabolism was examined with recombinant-expressed CYP1A2. 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, in log D by 3 log units, and in size of the added substituents. N-Dealkylation and aromatic hydroxylation (formation of the 4'- and 5'-regioisomers) were catalyzed by CYP1A2. Correlations of the metabolic kinetic parameters K(m) and catalytic efficiency (k(cat)/K(m)) with physicochemical properties pK(a) and log D showed that increased lipophilicity (higher log D values) was associated with increased affinity (lower K(m)) and increased catalytic efficiency for CYP1A2. Comparison of log K(m) and log k(cat)/K(m) with pK(a) showed that the less basic analogs had higher affinities and increased catalytic efficiencies. The changes associated with pK(a) reflect increased lipid partitioning of substrate (increased log D) caused by an increase in the proportion of nonionized substrate. Increased steric bulk in the N-substituent alone did not decrease substrate affinity for CYP1A2 but did increase the amount of aromatic hydroxylation versus N-dealkylation. Removal of the hydroxyl group from the propanolamine side chain of propranolol resulted in a similar change in regioselectivity of metabolism.
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 / Q000235:genetics; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism*; D017611:Fluorine Compounds / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D011433:Propranolol / Q000031:analogs & derivatives / Q000378:metabolism*
D000319:Adrenergic beta-Antagonists; D000588:Amines; D017611:Fluorine Compounds; D011433:Propranolol; D019388:Cytochrome P-450 CYP1A2