Synthesis and Structure‐Activity Relationships of 3H‐Quinazolin‐4‐ones and 3H‐Pyrido[2,3‐d]pyrimidin‐4‐ones as CXCR3 receptor antagonists
Synthesis and Structure‐Activity Relationships of 3H‐Quinazolin‐4‐ones and 3H‐Pyrido[2,3‐d]pyrimidin‐4‐ones as CXCR3 receptor antagonists
复制标题
CXCR3受体拮抗剂3H-喹唑啉-4-酮和3H-吡啶并[2,3-d]嘧啶-4-酮的合成及构效关系
作者：
S. Storelli;D. Verzijl;Jawad Al;N. Elders;Leontien Bosch;H. Timmerman;M. Smit;I. D. de Esch;R. Leurs
CXC 趋化因子受体 3 (CXCR3) 是一种 G 蛋白偶联受体 (GPCR)，主要表达在促进 Th1 反应的活化 T 淋巴细胞上。之前，我们描述了含有VUF 5834（癸酸{1-[3-(4-氰基-苯基)-4-氧代-3,4-二氢-喹唑啉-2-基]-乙基}-(2-二甲氨基-乙基)-酰胺）的3H-喹唑啉-4-酮作为小分子CXCR3拮抗剂 亚微摩尔亲和力并作为开发 CXCR3 拮抗剂的先导结构。最近，相关的 3H-吡啶并[2,3-d]嘧啶-4-酮化合物 AMG 487 和 NBI-74330 已被报道为纳摩尔 CXCR3 拮抗剂，这些配体目前正在临床研究中。本研究的目的是将先前发表的含有 CXCR3 配体的 3H-quinazolin-4-one 类的构效关系 (SAR) 与这些新型临床候选药物联系起来。从先导结构 VUF 5834 的修饰中可以看出，(4-氟-3-(三氟甲基)苯基)乙酰基和 3-亚甲基-吡啶作为取代基对于提高与人 CXCR3 受体的亲和力的重要性，而其他特征则不太重要。所描述的分子可作为研究 CXCR3 受体在各种炎症条件下作用的工具。
CXC chemokine receptor‐3 (CXCR3) is a G‐protein coupled receptor (GPCR) predominantly expressed on activated T lymphocytes that promote Th1 responses. Previously, we described the 3H‐quinazolin‐4‐one containing VUF 5834 (decanoic acid {1‐[3‐(4‐cyano‐phenyl)‐4‐oxo‐3,4‐dihydro‐quinazolin‐2‐yl]‐ethyl}‐(2‐dimethylamino‐ethyl)‐amide) as a small‐molecule CXCR3 antagonist with submicromolar affinity and as a lead structure for the development of CXCR3 antagonists. More recently, the related 3H‐pyrido[2,3‐d]pyrimidin‐4‐one compounds AMG 487 and NBI‐74330 have been reported as nanomolar CXCR3 antagonists and these ligands are currently under clinical investigation. The aim of this study is to link the structure‐activity relationship (SAR) of the previously published class of 3H‐quinazolin‐4‐one containing CXCR3 ligands with these novel clinical candidates. From the modification of the lead structure VUF 5834 emerged the importance of the (4‐fluoro‐3‐(trifluoromethyl)phenyl)acetyl and the 3‐methylen‐pyridine as substituents to improve the affinity at the human CXCR3 receptor, whereas other features are less important. The described molecules serve as tool to investigate the role of the CXCR3 receptor in various inflammatory conditions.
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影响因子：
21.1
作者：
P. Murphy;M. Baggiolini;I. Charo;C. Hébert;R. Horuk;K. Matsushima;L. Miller;J. Oppenheim;C. Power-C.
通讯作者：
P. Murphy;M. Baggiolini;I. Charo;C. Hébert;R. Horuk;K. Matsushima;L. Miller;J. Oppenheim;C. Power-C.
影响因子：
15.9
作者：
Mach, F;Sauty, A;Luster, AD
通讯作者：
Luster, AD
影响因子：
8.6
作者：
Patel, DD;Zachariah, JP;Whichard, LP
通讯作者：
Whichard, LP
影响因子：
11.2
作者：
Walser, Tonya C.;Rifat, Salah;Fulton, Amy M.
通讯作者：
Fulton, Amy M.
DOI：
10.1073/pnas.96.12.6873
发表时间：
1999-06-08
影响因子：
11.1
作者：
Balashov, KE;Rottman, JB;Hancock, WW
通讯作者：
Hancock, WW