一系列新型的补体成分C1s的芳基磺酰基噻吩-2-甲脒抑制剂。
A novel series of arylsulfonylthiophene-2-carboxamidine inhibitors of the complement component C1s.
作者信息
Subasinghe Nalin L, Travins Jeremy M, Ali Farah, Huang Hui, Ballentine Shelley K, Marugán Juan José, Khalil Ehab, Hufnagel Heather R, Bone Roger F, DesJarlais Renee L, Crysler Carl S, Ninan Nisha, Cummings Maxwell D, Molloy Christopher J, Tomczuk Bruce E
机构信息
Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 665 Stockton Drive, Exton, PA 19341, USA.
出版信息
Bioorg Med Chem Lett. 2006 Apr 15;16(8):2200-4. doi: 10.1016/j.bmcl.2006.01.036. Epub 2006 Feb 3.
Inhibiting the classical pathway of complement activation by attenuating the proteolytic activity of the serine protease C1s is a potential strategy for the therapeutic intervention in disease states such as hereditary angioedema, ischemia-reperfusion injury, and acute transplant rejection. A series of arylsulfonylthiophene-2-carboxamidine inhibitors of C1s were synthesized and evaluated for C1s inhibitory activity. The most potent compound had a Ki of 10nM and >1000-fold selectivity over uPA, tPA, FX(a), thrombin, and plasmin.
通过减弱丝氨酸蛋白酶C1s的蛋白水解活性来抑制补体激活的经典途径，是对遗传性血管性水肿、缺血再灌注损伤和急性移植排斥等疾病状态进行治疗干预的潜在策略。合成了一系列C1s的芳基磺酰基噻吩-2-甲脒抑制剂，并对其C1s抑制活性进行了评估。最有效的化合物对尿激酶型纤溶酶原激活剂（uPA）、组织型纤溶酶原激活剂（tPA）、活化因子X（FX(a)）、凝血酶和纤溶酶的抑制常数（Ki）为10nM，选择性大于1000倍。
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