Racemisation of drug enantiomers by benzylic proton abstraction at physiological pH.
The enantiomers of the aromatase inhibitors 3-(4-aminophenyl)-pyrrolidine-2,5-dione (WSP-3, II), its N-pentyl derivative (III), and the antifungal econazole (IV), all possessing a benzylic proton at the chiral centre, are rapidly racemised in vitro in phosphate buffer (0.01 M) at pH 7.4 and 23 degrees C with t 1/2 values of 7, 6, and 5 h respectively. In vivo studies in rats show that (+)-econazole is racemised after intraperitoneal injection with t 1/2 = 1.24h. The enantiomers of the antifungal 1-[(benzofuran-2-yl)-4-chlorophenylmethyl] imidazole (V) were stable at pH 7.4, attributable to steric hindrance to carbanion formation in the racemisation step.
Pepper
C
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Welsh School of Pharmacy, University of Wales College of Cardiff, U.K.
Smith
H J
HJ
Barrell
K J
KJ
Nicholls
P J
PJ
Hewlins
M J
MJ
D000814:Aniline Compounds / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D000818:Animals; D047072:Aromatase Inhibitors; D002021:Buffers; D004464:Econazole / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D010710:Phosphates; D011522:Protons; D011760:Pyrrolidinones / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013388:Succinimides / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology
C086122:1-pentyl-3-(4-aminophenyl)pyrrolidine-2,5-dione; D000814:Aniline Compounds; D047072:Aromatase Inhibitors; D002021:Buffers; D010710:Phosphates; D011522:Protons; D011760:Pyrrolidinones; D013388:Succinimides; C082712:3-(4'-aminophenyl)pyrrolidine-2,5-dione; D004464:Econazole