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具有治疗癌症、关节炎和心血管疾病功效的口服活性 MMP-1 保护的 α-四氢吡喃基和 α-哌啶基砜基质金属蛋白酶 (MMP) 抑制剂。

Orally active MMP-1 sparing α-tetrahydropyranyl and α-piperidinyl sulfone matrix metalloproteinase (MMP) inhibitors with efficacy in cancer, arthritis, and cardiovascular disease.

机构信息

Pfizer Research, 700 Chesterfield Village Parkway, St. Louis, Missouri 63198, USA.

出版信息

J Med Chem. 2010 Sep 23;53(18):6653-80. doi: 10.1021/jm100669j.

DOI:10.1021/jm100669j
PMID:20726512
Abstract

α-Sulfone-α-piperidine and α-tetrahydropyranyl hydroxamates were explored that are potent inhibitors of MMP's-2, -9, and -13 that spare MMP-1, with oral efficacy in inhibiting tumor growth in mice and left-ventricular hypertrophy in rats and in the bovine cartilage degradation ex vivo explant system. α-Piperidine 19v (SC-78080/SD-2590) was selected for development toward the initial indication of cancer, while α-piperidine and α-tetrahydropyranyl hydroxamates 19w (SC-77964) and 9i (SC-77774), respectively, were identified as backup compounds.

摘要

α-砜-α-哌啶和α-四氢吡喃基羟胺类化合物被探索出来，它们是 MMP-2、-9 和 -13 的强效抑制剂，对 MMP-1 具有选择性，在抑制小鼠肿瘤生长、大鼠左心室肥厚和牛软骨降解的离体组织系统中具有口服疗效。α-哌啶 19v（SC-78080/SD-2590）被选为癌症初始适应症的开发药物，而 α-哌啶和α-四氢吡喃基羟胺类化合物 19w（SC-77964）和 9i（SC-77774）则分别被确定为备用化合物。

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