Kinetics and mechanism of the hydrolytic degradation of indinavir: intramolecular catalysis.
The pH-rate profile of first-order rate constants for the lactonization of Indinavir in aqueous solutions with ionic strength I = 1 (KCl) at 40 degrees C is reported. The lactonization reaction is a subject of strong buffer catalysis with a nonlinear dependence of the first-order rate constants on the concentration of the buffer. The pH-rate profile is more complex than the pH-rate profiles for the hydrolysis of simple peptides and for the intramolecular OH-catalyzed hydrolysis of gamma-hydroxyamides. This complexity appears unique to Indinavir and is a result of the cis-aminoindanol leaving group. The mechanistic pathways for the lactonization are discussed. The buffer catalysis data are consistent with kinetic general acid catalysis. The second-order rate constant for the specific-acid catalyzed hydrolysis of Indinavir at 40 degrees C (k(H) = 2.2 x 10(-4) M(-1) min(-1)) is similar to that for a simple peptide indicating similar interactions in the rate limiting transition state for both reactions.
Toteva
Maria M
MM
Department of Pharmaceutics, Amgen Inc, 1110 Veterans Blvd, South San Francisco, California 94080, USA. mtoteva@amgen.com
Zanon
Roger
R
Ostovic
Drazen
D
D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D019469:Indinavir / Q000737:chemistry*; D007700:Kinetics; D013056:Spectrophotometry, Ultraviolet
D017320:HIV Protease Inhibitors; D019469:Indinavir