N-terminal 4-imidazolidinone prodrugs of Leu-enkephalin: synthesis, chemical and enzymatic stability studies

Four N-terminal 4-imidazolidinone prodrugs of Leu-enkephalin are prepared a nd characterized. Their enzymatic and chemical stability are assessed using high-performance liquid chromatography. The prodrug derivatives are shown to degrade stoichiometrically to Leu-enkephalin in phosphate buffer [t(1/2) (0.05 M phosphate buffer without KCl): acetone prodrug (II) 930 min; cyclo pentanone prodrug (LII): 216 min; cyclohexanone prodrug (IV): 432 min; 4-me thylcyclohexanone prodrug (V): 792 min]. Furthermore, the prodrugs are show n to afford global stabilization of the Leu-enkephalin molecule towards the enzymes, aminopeptidase N and angiotensin converting enzyme, primarily res ponsible for degradation of Leu-enkephalin at the blood-brain barrier and i n plasma. Therefore, the 4-imidazolidinones, being metabolic stable and bio reversible, may be suitable prodrug candidates for delivery of Leu-enkephal in to important target areas such as the brain, if given intravenously. (C) 1999 Elsevier Science B.V. All rights reserved.