Huang Shih-Chung, Undem Bradley, Korlipara Vijaya
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, NY 11439, USA.
Bioorg Med Chem Lett. 2004 Sep 20;14(18):4779-82. doi: 10.1016/j.bmcl.2004.06.053.
A series of N-methylbenzamide analogues (2-18) that is structurally derived from SR 48,968, a potent neurokinin-2 (NK(2)) receptor antagonist (pK(b)9.1), has been obtained using asymmetric synthesis. Isothiocyanato-N-methylbenzamide (10-12) and bromoacetamido-N-methylbenzamide derivatives (16-18) have been designed to serve as potential electrophilic affinity labels. Nitro-N-methylbenzamide (4-6) and acetamido-N-methylbenzamide (13-15) were designed to serve as the nonelectrophilic controls for these ligands. Functional assay results using guinea pig trachea indicate that electrophilic N-methylbenzamide analogues exhibit potent but surmountable NK(2) receptor antagonist activity. Several members of this series (2, 3, 7-9) exhibit potent NK(2) receptor antagonist potencies with pK(b) values in the range of 9.1-9.7. para-Fluoro substituted analogue 3 was found to be highly potent with a pK(b) of 9.7.
通过不对称合成得到了一系列结构上衍生自强效神经激肽 -2（NK(2)）受体拮抗剂SR 48,968（pK(b) 9.1）的N - 甲基苯甲酰胺类似物（2 - 18）。异硫氰酸根合 - N - 甲基苯甲酰胺（10 - 12）和溴乙酰胺基 - N - 甲基苯甲酰胺衍生物（16 - 18）被设计用作潜在的亲电亲和标记物。硝基 - N - 甲基苯甲酰胺（4 - 6）和乙酰氨基 - N - 甲基苯甲酰胺（13 - 15）被设计用作这些配体的非亲电对照物。使用豚鼠气管进行的功能测定结果表明，亲电N - 甲基苯甲酰胺类似物表现出强效但可克服的NK(2)受体拮抗剂活性。该系列中的几个成员（2、3、7 - 9）表现出强效的NK(2)受体拮抗效力，pK(b)值在9.1 - 9.7范围内。发现对氟取代类似物3具有高度效力，pK(b)为9.7。
