识别小说绑定交互发展的强大,尿激酶的选择性2-naphthamidine抑制剂。合成、结构分析、和得酰胺6-substitution SAR。

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比医学博士Rockway TW,盖尔,麦克莱伦W, Weitzberg M,赵X, Mantei R, Nienaber六世,斯图尔特K, Klinghofer V, Giranda六世

识别小说绑定交互发展的强大,尿激酶的选择性2-naphthamidine抑制剂。合成、结构分析、和得酰胺6-substitution SAR。

J地中海化学。2004年1月15;47 (2):303 - 24。

PubMed ID

14711304 (在PubMed

]

文摘

生物活性的准备和评估6-substituted 2-naphthamidine丝氨酸蛋白酶的抑制剂尿激酶纤溶酶原激活物(uPA或尿激酶)。2-Naphthamidine被选为一个起点,基于综合考虑建模的取代基向量。苯酰胺在6-position发现改善绑定;与其他两个atom取代酰胺基团被证明是无效的。苯基本身坐落在S1 '子站;替换的苯基S1 '和其他遥远的约束力的地区访问。三个新的交互点定义和探索通过环替换。solvent-exposed盐桥与Asp60A羧酸盐使用4-alkylamino集团成立,提高亲和力K (i) = 40 nM。抑制剂还访问两个疏水区域。一种互动的特点是严格疏水适合用小酒窝主要由His57 His99; a weaker, less specific interaction involves alkyl groups reaching into the broad prime-side protein binding region near Val41 and the Cys42-Cys58 disulfide, displacing water molecules and leading to small gains in activity. Many inhibitors accessed two of these three regions. Affinities range as low as K(i) = 6 nM, and many compounds had K(i) < 100 nM, while moderate to excellent selectivity was gained versus four of five members of a panel of relevant serine proteases. Also, some selectivity against trypsin was generated via the interaction with Asp60A. X-ray structures of many of these compounds were used to inform our inhibitor design and to increase our understanding of key interactions. In combination with our exploration of 8-substitution patterns, we have identified a number of novel binding interactions for uPA inhibitors.

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绑定属性

药物	目标	财产	测量	pH值	温度(°C)
(6)- N-Phenylcarbamyl 2-naphthalenecarboxamidine	Urokinase-type纤溶酶原激活物	Ki (nM)	631年	N /一个	N /一个	细节
6 - [(Z)氨基(亚氨基的)甲基]- n - [3 - (CYCLOPENTYLOXY)苯基]2-naphthamide	Urokinase-type纤溶酶原激活物	Ki (nM)	28	N /一个	N /一个	细节
6 - [N - (1-Isopropyl-1 2 3, 4-Tetrahydro-7-Isoquinolinyl)氨基甲酰)2-naphthalenecarboxamidine	Urokinase-type纤溶酶原激活物	Ki (nM)	23.5	N /一个	N /一个	细节
6 - [N - (1-Isopropyl-3 4-Dihydro-7-Isoquinolinyl)氨基甲酰)2-naphthalenecarboxamidine	Urokinase-type纤溶酶原激活物	Ki (nM)	48	N /一个	N /一个	细节
6 - [N -(4 -(氨甲基)苯基)氨基甲酰)2-naphthalenecarboxamidine	Urokinase-type纤溶酶原激活物	Ki (nM)	40	N /一个	N /一个	细节
6 - [N - (4-Ethyl-1 2 3, 4-Tetrahydro-6-Isoquinolinyl)氨基甲酰)2-naphthalenecarboxamidine	Urokinase-type纤溶酶原激活物	Ki (nM)	6.3	N /一个	N /一个	细节