Synthesis and structure-activity relationships of β- and α-piperidine sulfone hydroxamic acid matrix metalloproteinase inhibitors with oral antitumor efficacy
Synthesis and structure-activity relationships of β- and α-piperidine sulfone hydroxamic acid matrix metalloproteinase inhibitors with oral antitumor efficacy
复制标题
DOI：
10.1021/jm0500875
复制
发表时间：
2005-10-20
影响因子：
7.3
通讯作者：
Swearingen, CA
中科院分区：
文献类型：
--
作者：
Becker, DP;Villamil, CI;Swearingen, CA
研究了α-曲马定-β-砜异羟肟酸酯衍生物，其对基质金属蛋白酶（MMP）-2、-9和-13是有效的，而不含MMP-1。对β-砜的研究随后发现了迄今为止未知的α-砜异羟肟酸盐，这些异羟肟酸盐在靶向MMP的效力、对MMP-1的选择性以及口服给药时的暴露量方面优于相应的β-砜，这些异羟肟酸盐具有上级。α-替哌啶-α-砜，异羟肟酸盐35 f（SC-276）通过抗肿瘤和抗血管生成试验进行了改进，并被选择用于开发。当作为单一疗法或与紫杉醇组合口服给药时，化合物35 f在小鼠中相对于MX-1乳腺肿瘤表现出优异的抗肿瘤活性。
alpha-Piperidine-beta-sulfone hydroxamate derivatives were explored that are potent for matrix metalloproteinases (MMP)-2, -9, and -13 and are sparing of MMP-1. The investigation of the beta-sulfones subsequently led to the discovery of hitherto unknown alpha-sulfone hydroxamates that are superior to the corresponding beta-sulfones in potency for target MMPs, selectivity vs MMP-1, and exposure when dosed orally. alpha-Tiperidine-alpha-sulfone, hydroxamate 35f (SC-276) was advanced through antitumor and antiangiogenesis assays and was selected for development. Compound 35f demonstrates excellent antitumor activity vs MX-1 breast tumor in mice when dosed orally as monotherapy or in combination with paclitaxel.