DEGRADATION OF A NOVEL TRIPEPTIDE, TERT-BUTOXYCARBONYL-TYR-LEU-VAL-CH2CL, WITH INHIBITORY EFFECT ON HUMAN-LEUKOCYTE ELASTASE IN AQUEOUS-SOLUTION AND IN BIOLOGICAL-FLUIDS

The stability of tert-butoxycarbonyl-Tyr-Leu-Val-CH2 Cl (YLV) with inh ibitory effect on human leukocyte elastase was investigated in aqueous solution, a-chymotrypsin solution and biological media, In all cases studied here, the degradation was observed as a pseudo-first order rea ction, The half-life for the degradation of YLV in an aqueous solution of pH 7.4 at 37 degrees C was 35.9 h. YLV was most stable at about pH 3.8-5.8 and the effect of temperature was explained by the Arrhenius equation, The activation energies of the degradation in aqueous soluti ons at pH 2.0, 4.8, and 7.4 were 24.6, 22.1 and 23.4 kcal/mol, respect ively, The degradation products in aqueous solution were analyzed by H PLC-MS and were estimated as Boc-Tyr-Leu-Val-CH2OH at pH 7.4 and H2N-T yr-Leu-Val-CH2Cl at pH 2.0. In a bovine pancreas alpha-chymotrypsin so lution at 37 degrees C, the half-life of nV was 15 min at 25.6 mu g/ml of alpha-chymotrypsin solution, In the rat plasma, the half-life of Y LV was 42.4 min (nV 26.7 mu g/ml plasma), and in rat liver, lung and s pleen homogenates, the degradation rate constants of YLV were 37.6, 10 .3 and 23.5 times larger than that in plasma solution, respectively (a ll fluids containing 5 mg protein/ml). YLV was less stable than nafare lin acetate, secretin, adrenocorticotropic hormone (ACTH) and gonadore lin in an aqueous solution of pH 7.4.