发现3-哌啶基-1-环戊烷甲酰胺作为一种新型高效CC趋化因子受体2拮抗剂的骨架。
Discovery of 3-piperidinyl-1-cyclopentanecarboxamide as a novel scaffold for highly potent CC chemokine receptor 2 antagonists.
作者信息
Yang Lihu, Butora Gabor, Jiao Richard X, Pasternak Alex, Zhou Changyou, Parsons William H, Mills Sander G, Vicario Pasquale P, Ayala Julia M, Cascieri Margaret A, MacCoss Malcolm
机构信息
Merck Research Laboratories, Rahway, New Jersey 07065, USA.
出版信息
J Med Chem. 2007 May 31;50(11):2609-11. doi: 10.1021/jm070166b. Epub 2007 Apr 27.
Introduction of ring restrictions to a linear aminobutyramide CC chemokine receptor 2 (CCR2) antagonist lead (2) led to the discovery of a 1,3-disubstituted cyclopentane scaffold with enhanced hCCR2 receptor binding and antagonist activity. (1S,3R)-N-[3,5-Bis(trifluoromethyl)benzyl]-1-methyl-3-[(1R,3'R)-methyl-1'H-spiro[indene-1,4'-piperidin]-1'-yl]cyclopentanecarboxamide (16) had IC50 of 1.3 nM (binding) and 0.45 nM (functional chemotaxis) against hCCR2. It also showed activity against the mouse CCR2 receptor with an IC50 of 130 nM. Compound 16 is selective against other chemokine receptors, including CCR5 ( approximately 500-fold).
将环限制引入线性氨基丁酰胺CC趋化因子受体2（CCR2）拮抗剂先导物（2），从而发现了一种具有增强的人CCR2受体结合力和拮抗剂活性的1,3 - 二取代环戊烷骨架。(1S,3R)-N-[3,5-双(三氟甲基)苄基]-1-甲基-3-[(1R,3'R)-甲基-1'H-螺[茚-1,4'-哌啶]-1'-基]环戊烷甲酰胺（16）对人CCR2的IC50为1.3 nM（结合）和0.45 nM（功能性趋化作用）。它对小鼠CCR2受体也有活性，IC50为130 nM。化合物16对其他趋化因子受体具有选择性，包括CCR5（约500倍）。
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