Wagner B M, Smith R A, Coles P J, Copp L J, Ernest M J, Krantz A
Department of Lipid and Protease Biochemistry, Syntex Research, Palo Alto, California 94304.
J Med Chem. 1994 Jun 10;37(12):1833-40. doi: 10.1021/jm00038a012.
Peptidyl (acyloxy)methyl ketones, previously established as potent irreversible inhibitors of the cysteine proteinase cathepsin B in vitro, were investigated and optimized for their inhibitory activity in vivo. Incorporation of polar or charged functional groups in the inhibitor structure afforded effective cathepsin B inhibition, following dosing to rats. The most effective inhibitor, Z-Phe-Lys-CH2OCO-(2,4,6-Me3)Ph (8), was found to give ED50 values of 18 mg/kg po (orally) and 5.0 mg/kg ip (intraperitoneally) at 4-5 h postdose, and 2.4 mg/kg sc (subcutaneously) at 24 h postdose, for liver cathepsin B inhibition (measured ex vivo). The subcutaneous route of administration of (acyloxy)methyl ketone 8 also provided potent cathepsin B inhibition in certain peripheral tissues (e.g., ED50 1.0 mg/kg for skeletal muscle, 0.1 mg/kg for heart). These investigations demonstrate that peptidyl (acyloxy)methyl ketones such as 8 have promise as tools for the characterization of in vivo biochemical processes and as therapeutic agents.
肽基（酰氧基）甲基酮类化合物，此前已被证实为半胱氨酸蛋白酶组织蛋白酶B的强效不可逆体外抑制剂，本研究对其体内抑制活性进行了考察和优化。在抑制剂结构中引入极性或带电荷的官能团后，对大鼠给药后可有效抑制组织蛋白酶B。发现最有效的抑制剂Z-Phe-Lys-CH2OCO-(2,4,6-Me3)Ph（8）在给药后4-5小时，口服的ED50值为18mg/kg，腹腔注射为5.0mg/kg，给药后24小时皮下注射的ED50值为2.4mg/kg，用于抑制肝脏组织蛋白酶B（离体测定）。（酰氧基）甲基酮8皮下给药在某些外周组织中也能有效抑制组织蛋白酶B（例如，骨骼肌的ED50为1.0mg/kg，心脏的ED50为0.1mg/kg）。这些研究表明，诸如8这类肽基（酰氧基）甲基酮有望作为表征体内生化过程的工具和治疗药物。
