Janusz M J, Hookfin E B, Brown K K, Hsieh L C, Heitmeyer S A, Taiwo Y O, Natchus M G, Pikul S, Almstead N G, De B, Peng S X, Baker T R, Patel V
Procter & Gamble Pharmaceuticals Inc., 8700 Mason-Montgomery Rd., Mailbox 1069, Mason, OH 45040-9462, USA.
Inflamm Res. 2006 Feb;55(2):60-5. doi: 10.1007/s00011-005-0014-4.
Hydroxamic-and carboxylic-acid based matrix metalloproteinase inhibitors (MMPIs) were compared for their potency against various MMPs, pharmacodynamic properties and in vivo efficacy in a model of cartilage degeneration.
The MMPIs were evaluated for their ability to inhibit human MMPs using the quenched fluorescence assay. The ability of the MMPIs to inhibit the degeneration of the knee joint was evaluated in rats injected intraarticularly with iodoacetate. The amount of MMPI in the plasma and cartilage was determined using liquid chromatography/mass spectrometry/mass spectrometry (LC/ MS/MS). Plasma protein binding was measured by ultrafiltration and unbound MMPI was quantitated using HPLC.
The hydroxamic acid based inhibitor PGE-3321996 and the carboxylic acids PGE-2909492 and PGE-6292544 were potent MMP-13 inhibitors, but only the hydroxamic acid PGE 3321996 demonstrated significant inhibition of knee degeneration in the rat iodoacetate model. Both of the carboxylic acids demonstrated superior pharmacokinetic properties and established much higher plasma concentrations than the hydroxamic acid. However, neither of the carboxylic acids was detectable in the cartilage, whereas, the hydroxamic acid was present in both the cartilage and the plasma. The carboxylic acid based MMPIs also demonstrated higher plasma protein binding (>99%) than the hydroxamic acid (79%).
Carboxylic acid-based MMPIs were identified that had superior in vivo plasma exposure compared to a hydroxamic acid inhibitor but lacked in vivo efficacy in the rat iodoacetate model of cartilage degeneration. The lack of in vivo efficacy of the carboxylic acid based MMPIs were probably due to their lack of cartilage penetration which was related to their physicochemical properties.
比较基于异羟肟酸和羧酸的基质金属蛋白酶抑制剂（MMPIs）对各种基质金属蛋白酶（MMPs）的抑制效力、药效学特性以及在软骨退变模型中的体内疗效。
使用淬灭荧光测定法评估MMPIs抑制人MMPs的能力。在关节内注射碘乙酸的大鼠中评估MMPIs抑制膝关节退变的能力。使用液相色谱/质谱/质谱（LC/MS/MS）测定血浆和软骨中MMPI的含量。通过超滤测量血浆蛋白结合率，并使用高效液相色谱（HPLC）对未结合的MMPI进行定量。
基于异羟肟酸的抑制剂PGE - 3321996以及羧酸PGE - 2909492和PGE - 6292544是有效的MMP - 13抑制剂，但只有异羟肟酸PGE 3321996在大鼠碘乙酸模型中显示出对膝关节退变的显著抑制作用。两种羧酸均表现出更优的药代动力学特性，且血浆浓度比异羟肟酸高得多。然而，在软骨中均未检测到这两种羧酸，而异羟肟酸同时存在于软骨和血浆中。基于羧酸的MMPIs的血浆蛋白结合率也高于异羟肟酸（>99%比79%）。
已鉴定出基于羧酸的MMPIs，其在体内的血浆暴露量优于异羟肟酸抑制剂，但在大鼠碘乙酸软骨退变模型中缺乏体内疗效。基于羧酸的MMPIs缺乏体内疗效可能是由于它们缺乏软骨穿透性，这与其物理化学性质有关。
