Gonsiorek Waldemar, Fan Xuedong, Hesk David, Fossetta James, Qiu Hongchen, Jakway James, Billah Motasim, Dwyer Michael, Chao Jianhua, Deno Gregory, Taveras Art, Lundell Daniel J, Hipkin R William
Department of Inflammation, K15 E332C-3945, Schering-Plough Research Institute, 2015 Galloping Hill Rd, Kenilworth, NJ 07033-0539, USA.
J Pharmacol Exp Ther. 2007 Aug;322(2):477-85. doi: 10.1124/jpet.106.118927. Epub 2007 May 11.
In neutrophils, growth-related protein-alpha (CXCL1) and interleukin-8 (CXCL8), are potent chemoattractants (Cytokine 14:27-36, 2001; Biochemistry 42:2874-2886, 2003) and can stimulate myeloperoxidase release via activation of the G protein-coupled receptors CXCR1 and CXCR2. The role of CXCR1 and CXCR2 in the pathogenesis of inflammatory responses has encouraged the development of small molecule antagonists for these receptors. The data presented herein describe the pharmacology of 2-hydroxy-N,N-dimethyl-3-{2-[[(R)-1-(5-methyl-furan-2-yl)-propyl]amino]-3,4-dioxo-cyclobut-1-enylamino}-benzamide (Sch527123), a novel antagonist of both CXCR1 and CXCR2. Sch527123 inhibited chemokine binding to (and activation of) these receptors in an insurmountable manner and, as such, is categorized as an allosteric antagonist. Sch527123 inhibited neutrophil chemotaxis and myeloperoxidase release in response to CXCL1 and CXCL8 but had no effect on the response of these cells to C5a or formyl-methionyl-leucyl-phenylalanine. The pharmacological specificity of Sch527123 was confirmed by testing in a diversity profile against a panel of enzymes, channels, and receptors. To measure compound affinity, we characterized [(3)H]Sch527123 in both equilibrium and nonequilibrium binding analyses. Sch527123 binding to CXCR1 and CXCR2 was both saturable and reversible. Although Sch527123 bound to CXCR1 with good affinity (K(d) = 3.9 +/- 0.3 nM), the compound is CXCR2-selective (K(d) = 0.049 +/- 0.004 nM). Taken together, our data show that Sch527123 represents a novel, potent, and specific CXCR2 antagonist with potential therapeutic utility in a variety of inflammatory conditions.
在中性粒细胞中，生长相关蛋白α（CXCL1）和白细胞介素-8（CXCL8）是强效趋化因子（《细胞因子》14:27 - 36，2001；《生物化学》42:2874 - 2886，2003），可通过激活G蛋白偶联受体CXCR1和CXCR2刺激髓过氧化物酶释放。CXCR1和CXCR2在炎症反应发病机制中的作用促使了针对这些受体的小分子拮抗剂的研发。本文呈现的数据描述了2 - 羟基 - N，N - 二甲基 - 3 - {2 - [[(R) - 1 - (5 - 甲基 - 呋喃 - 2 - 基) - 丙基]氨基] - 3，4 - 二氧代 - 环丁 - 1 - 烯基氨基} - 苯甲酰胺（Sch527123）的药理学特性，它是一种新型的CXCR1和CXCR2双重拮抗剂。Sch527123以不可克服的方式抑制趋化因子与这些受体的结合（以及对其的激活），因此被归类为变构拮抗剂。Sch527123抑制中性粒细胞趋化以及对CXCL1和CXCL8产生的髓过氧化物酶释放，但对这些细胞对C5a或甲酰 - 甲硫氨酰 - 亮氨酰 - 苯丙氨酸的反应没有影响。通过针对一系列酶、通道和受体的多样性谱测试，证实了Sch527123的药理学特异性。为了测量化合物亲和力，我们在平衡和非平衡结合分析中对[(3)H]Sch527123进行了表征。Sch527123与CXCR1和CXCR2的结合是可饱和且可逆的。虽然Sch527123与CXCR1具有良好的亲和力（K(d) = 3.9 ± 0.3 nM），但该化合物对CXCR2具有选择性（K(d) = 0.049 ± 0.004 nM）。综上所述，我们的数据表明Sch527123是一种新型、强效且特异性的CXCR2拮抗剂，在多种炎症性疾病中具有潜在的治疗效用。
