Use of a dipeptide chemical library in the development of non-peptide tachykinin NK3 receptor selective antagonists
Use of a dipeptide chemical library in the development of non-peptide tachykinin NK3 receptor selective antagonists
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DOI：
10.1021/jm950892r
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发表时间：
1996-04-12
影响因子：
7.3
通讯作者：
Woodruff, GN
中科院分区：
文献类型：
--
作者：
Boden, P;Eden, JM;Woodruff, GN
描述了将二肽库用作人速激肽NK3受体的微摩尔化学先导化合物的来源。通过克隆的人NK3受体结合实验筛选双肽文库，鉴定出Boc(S)Phe(S)PheNH(2)(1)，随后采用类肽设计策略将其开发为一系列高亲和力的NK3受体选择性拮抗剂。首次探索了该二肽先导化合物C-末端的构效关系，并鉴定为尿素衍生物Boc(S)Phe(R)αMePheNH(CH2)(7)NHCONH2(41，PD157672)。这种修饰的二肽具有7 nM的K-e，能阻断刺五加诱导CHO细胞稳定表达的人NK3受体细胞内钙水平的增加。随后对41的N-末端BocPhe基团和α-MePhe残基侧链进行了优化，得到了非肽NK3受体选择性拮抗剂[S-(R*，S*)]-[2-(2，3-difluorophenyl)-1-methyl-1-[(7-ureidoheptyl)carbamoyl]ethyl]carbamic酸2-甲基-1-苯丙酯(60，PD161182)])。化合物60可阻断激动剂引起的细胞内钙离子浓度的升高，使克隆的人NK3受体在CHO细胞中稳定表达，K-e为0.9 nM。
The use of a dipeptide library as the source of a micromolar chemical lead compound for the human tachykinin NK3 receptor is described. The screening of a dipeptide library through a cloned human NK3 receptor binding assay resulted in the identification of Boc(S)Phe(S)PheNH(2) (1), which has subsequently been developed, following a 'peptoid' design strategy, into a series of high-affinity NK3 receptor selective antagonists. The structure-activity relationship of the C-terminal portion of this dipeptide lead was first explored and led to the identification of the urea derivative Boc(S)Phe(R)alpha MePheNH(CH2)(7)NHCONH2 (41, PD157672). This modified dipeptide has a K-e of 7 nM in blocking senktide-induced increases in intracellular calcium levels in human NK3 receptors stably expressed in CHO cells. Subsequent optimization of the N-terminal BocPhe group and the alpha MePhe residue side chain of 41 led to the identification of [S-(R*,S*)]-[2-(2,3-difluorophenyl)-1-methyl-1-[(7-ureidoheptyl)carbamoyl]ethyl]carbamic acid 2-methyl-1-phenylpropyl ester (60, PD161182), a non-peptide NK3 receptor selective antagonist. Compound 60 blocks the senktide-evoked increases in intracellular calcium levels in cloned human NK3 receptors stably expressed in CHO cells with K-e of 0.9 nM.