Su Dai-Shi, Markowitz M Kristine, DiPardo Robert M, Murphy Kathy L, Harrell C Meacham, O'Malley Stacy S, Ransom Richard W, Chang Raymond S L, Ha Sookhee, Hess Fred J, Pettibone Douglas J, Mason Glenn S, Boyce Susan, Freidinger Roger M, Bock Mark G
Departments of Medicinal Chemistry and Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA.
J Am Chem Soc. 2003 Jun 25;125(25):7516-7. doi: 10.1021/ja0353457.
Bradykinin (BK) plays an important role in the pathophysiological processes accompanying pain and inflammation. Selective bradykinin B1 receptor antagonists have been shown to be anti-nociceptive in animal models and could be novel therapeutic agents for the treatment of pain and inflammation. We have explored chemical modifications in a series of dihydroquinoxalinone sulfonamides to evaluate the effects of various structural changes on biological activity. The optimization of a screening lead compound, facilitated by a homology model of the BK B1 receptor, culminated in the discovery of a potent human BK B1 receptor antagonist. Results from site-directed mutagenesis studies and experiments in an animal pain model are presented.
缓激肽（BK）在伴随疼痛和炎症的病理生理过程中起重要作用。选择性缓激肽B1受体拮抗剂在动物模型中已显示出抗伤害感受作用，可能成为治疗疼痛和炎症的新型治疗药物。我们对一系列二氢喹喔啉酮磺酰胺进行了化学修饰，以评估各种结构变化对生物活性的影响。通过BK B1受体的同源模型促进筛选先导化合物的优化，最终发现了一种有效的人BK B1受体拮抗剂。本文介绍了定点诱变研究结果和动物疼痛模型实验结果。
