Vol. 29, Issue 11, 1389-1395, November 2001

Importance of Amine pK_a and Distribution Coefficient in the Metabolism of Fluorinated Propranolol Analogs: Metabolism by CYP1A2

Alana L. Upthagrove and Wendel L. Nelson

Department of Medicinal Chemistry, University of Washington, Seattle, Washington

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.