Gütschow M, Neumann U
Institute of Pharmacy, University of Leipzig, D-04103 Leipzig, Germany, and Novartis Pharma AG, CH-4002 Basel, Switzerland.
J Med Chem. 1998 May 7;41(10):1729-40. doi: 10.1021/jm9708341.
A series of thieno[2,3-d][1,3]oxazin-4-ones was synthesized and evaluated in vitro for inhibitory activity toward human leukocyte elastase. New synthetic routes to 2-alkoxy-, 2-alkylthio-, and 2-sec-amino-substituted derivatives are reported. This study demonstrates the versatility of 2-aminothiophenes prepared by Gewald reaction as a synthetic entry to serine protease-inhibiting, fused 1,3-oxazin-4-ones. Introduction of ethoxy, n-propoxy, and ethylthio groups at C-2 delivered the most potent inhibitors of this series with Ki values lower than 11 nM. Kinetic studies and product analyses revealed the formation of acyl-enzymes as a result of the attack of the active site serine at the carbon C-4 and subsequent deacylation. This mode of action is similar to the inhibition of serine proteases by 4H-3,1-benzoxazin-4-ones. Replacement of the benzene ring in benzoxazinones by a (substituted) thiophene led to improved hydrolytic stability and retained inhibitory potency.
合成了一系列噻吩并[2,3 - d][1,3]恶嗪 - 4 - 酮，并在体外评估了它们对人白细胞弹性蛋白酶的抑制活性。报道了制备2 - 烷氧基、2 - 烷硫基和2 - 仲氨基取代衍生物的新合成路线。本研究证明了通过格瓦尔德反应制备的2 - 氨基噻吩作为合成丝氨酸蛋白酶抑制性稠合1,3 - 恶嗪 - 4 - 酮的起始原料的多功能性。在C - 2位引入乙氧基、正丙氧基和乙硫基得到了该系列中最有效的抑制剂，其Ki值低于11 nM。动力学研究和产物分析表明，由于活性位点丝氨酸攻击C - 4位碳原子并随后脱酰化，形成了酰基酶。这种作用方式类似于4H - 3,1 - 苯并恶嗪 - 4 - 酮对丝氨酸蛋白酶的抑制作用。用（取代的）噻吩取代苯并恶嗪酮中的苯环导致水解稳定性提高，同时保留了抑制效力。
