基质金属蛋白酶-13 抑制剂的开发——构效/构性关系研究。
Development of matrix metalloproteinase-13 inhibitors - A structure-activity/structure-property relationship study.
机构信息
Department of Chemistry, Scripps Florida, Jupiter, FL 33458, United States; Institute of Organic Chemistry, Graz University of Technology, 8010 Graz, Austria.
Department of Chemistry, Scripps Florida, Jupiter, FL 33458, United States; Department of Chemistry and Biochemistry, Queens College and the Graduate Center of the City University of New York, New York 11367, United States.
出版信息
Bioorg Med Chem. 2018 Oct 1;26(18):4984-4995. doi: 10.1016/j.bmc.2018.08.020. Epub 2018 Aug 20.
Abstract
A structure-activity/structure-property relationship study based on the physicochemical as well as in vitro pharmacokinetic properties of a first generation matrix metalloproteinase (MMP)-13 inhibitor (2) was undertaken. After systematic variation of inhibitor 2, compound 31 was identified which exhibited microsomal half-life higher than 20 min, kinetic solubility higher than 20 μM, and a permeability coefficient greater than 20 × 10 cm/s. Compound 31 also showed excellent in vivo PK properties after IV dosing (C = 56.8 μM, T (plasma) = 3.0 h, Cl = 0.23 mL/min/kg) and thus is a suitable candidate for in vivo efficacy studies in an OA animal model.
摘要
我们基于第一代基质金属蛋白酶（MMP）-13 抑制剂（2）的理化性质和体外药代动力学性质，进行了构效/构效关系研究。对抑制剂 2 进行系统改造后，发现化合物 31 具有超过 20 分钟的半衰期、超过 20 μM 的动力学溶解度和大于 20×10 cm/s 的渗透系数。化合物 31 在静脉给药后也表现出优异的体内 PK 性质（C=56.8 μM，T（血浆）=3.0 h，Cl=0.23 mL/min/kg），因此是在 OA 动物模型中进行体内疗效研究的合适候选药物。
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