Degradation of a Novel Tripeptide, tert-Butoxycarbonyl-Tyr-Leu-Val-CH_2Cl, with Inhibitory Effect on Human Leukocyte Elastase in Aqueous Solution and in Biological Fluids

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The stability of tert-butoxycarbonyl-Tyr-Leu-Val-CH_2Cl (YLV) with inhibitory effect of human leukocyte elastase was investigated in aqueous solution, α-chymotrypsin solution and biological media. In all cases studied here, the degradation was observed as a pseudo-first order reaction. The half-life for the degradation of YLV in an aqueous solution of pH 7.4 at 37℃ 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 solutions at pH 2.0,4.8,and 7.4 were 24.6,22.1 and 23.4 kcal/mol, respectively. The degradation products in aqueous solution were analyzed by HPLC-MS and were estimated as Boc-Tyr-Leu-Val-CH_2OH at pH 7.4 and H_2N-Tyr-Leu-Val-CH_2Cl at pH 2.0. In a bovine pancreas α-chymotrypsin solution at 37℃, the half-life and YLV was 15 min at 25.6 μg/ml of α-chymotrypsin solution. In the rat plasma, the half-life of YLV was 42.4 min (YLV 26.7 μg/ml plasma), and in rat liver, lung and spleen homogenates, the degradation rate constants of YLV were 37.6,10.3 and 23.5 times larger than that in plasma solution, respectively (all fluids containing 5 mg protein/ml).YLV was less stable than nafarelin acetate, secretin, adrenocorticotropic hormone (ACTH) and gonadorelin in an aqueous solution of pH 7.4.
公益社団法人日本薬学会の論文
1997-11-15