Cherney Robert J, Duan James J-W, Voss Matthew E, Chen Lihua, Wang Li, Meyer Dayton T, Wasserman Zelda R, Hardman Karl D, Liu Rui-Qin, Covington Maryanne B, Qian Mingxin, Mandlekar Sandhya, Christ David D, Trzaskos James M, Newton Robert C, Magolda Ronald L, Wexler Ruth R, Decicco Carl P
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
J Med Chem. 2003 May 8;46(10):1811-23. doi: 10.1021/jm020475w.
Elevated levels of tumor necrosis factor-alpha (TNF-alpha) have been associated with several inflammatory diseases, and therefore, strategies for its suppression have become important targets in drug discovery. Our efforts to suppress TNF-alpha have centered on the inhibition of TNF-alpha converting enzyme (TACE) through the use of hydroxamate inhibitors. Starting from broad-spectrum matrix metalloproteinase (MMP) inhibitors, we have designed and synthesized novel benzothiadiazepines as potent and selective TACE inhibitors. The benzothiadiazepines were synthesized with variation in P1 and P1' in order to effect potency and selectivity. The inhibitors were evaluated versus porcine TACE (pTACE), and the initial selectivity was assessed with counterscreens of MMP-1, -2, and -9. Several potent and selective inhibitors were discovered with compound 41 being the most active against pTACE (K(i) = 5 nM) while still maintaining good selectivity versus the MMP's (at least 75-fold). Most compounds were assessed in the human peripheral blood mononuclear cell assay (PBMC) and the human whole blood assay (WBA) to determine their ability to suppress TNF-alpha. Compound 32 was the most potent compound in the PBMC assay (IC(50) = 0.35 microM), while compound 62 was the most active in the WBA (IC(50) = 1.4 microM).
肿瘤坏死因子-α（TNF-α）水平升高与多种炎症性疾病相关，因此，抑制TNF-α的策略已成为药物研发的重要靶点。我们抑制TNF-α的工作主要集中在通过使用异羟肟酸酯抑制剂来抑制TNF-α转换酶（TACE）。从广谱基质金属蛋白酶（MMP）抑制剂出发，我们设计并合成了新型苯并噻二氮䓬类化合物作为强效且选择性的TACE抑制剂。合成苯并噻二氮䓬类化合物时，对P1和P1'进行了变化，以实现效力和选择性。对这些抑制剂针对猪TACE（pTACE）进行了评估，并通过MMP-1、-2和-9的反筛选评估了初始选择性。发现了几种强效且选择性的抑制剂，化合物41对pTACE活性最高（K(i)=5 nM），同时对MMP仍保持良好的选择性（至少75倍）。大多数化合物在人外周血单核细胞试验（PBMC）和人全血试验（WBA）中进行了评估，以确定它们抑制TNF-α的能力。化合物32在PBMC试验中是最有效的化合物（IC(50)=0.35 microM），而化合物62在WBA中活性最高（IC(50)=1.4 microM）。
