基于强效且具选择性的β-高苯丙氨酸的二肽基肽酶IV抑制剂的发现。
Discovery of potent and selective beta-homophenylalanine based dipeptidyl peptidase IV inhibitors.
作者信息
Xu Jinyou, Ok Hyun O, Gonzalez Edward J, Colwell Lawrence F, Habulihaz Bahanu, He Huaibing, Leiting Barbara, Lyons Kathryn A, Marsilio Frank, Patel Reshma A, Wu Joseph K, Thornberry Nancy A, Weber Ann E, Parmee Emma R
机构信息
Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
出版信息
Bioorg Med Chem Lett. 2004 Sep 20;14(18):4759-62. doi: 10.1016/j.bmcl.2004.06.099.
Modification of in-house screening lead beta-aminoacyl proline 8 gave an equipotent thiazolidide 9. Extensive SAR studies on the phenyl ring of 9 led to the discovery of a novel series of potent and selective DP-IV inhibitors. Introduction of a fluorine at the 2-position proved to be crucial for the potency of this series. The 2,5-difluoro (22q) and 2,4,5-trifluoro (22t) analogues were potent inhibitors of DP-IV (IC(50)=270, 119nM, respectively).
对内部筛选先导化合物β-氨基酰基脯氨酸8进行修饰得到了具有同等效力的噻唑烷二酮9。对9的苯环进行了广泛的构效关系研究，从而发现了一系列新型的强效和选择性二肽基肽酶-IV（DP-IV）抑制剂。结果证明在2-位引入氟对于该系列化合物的效力至关重要。2,5-二氟（22q）和2,4,5-三氟（22t）类似物是DP-IV的强效抑制剂（IC(50)分别为270、119 nM）。
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