title: Dipyrimidine amines: a novel class of chemokine receptor type 4 antagonists with high specificity.
abstract: The C-X-C chemokine receptor type 4 (CXCR4)/stromal cell derived factor-1 (SDF-1 or CXCL12) interaction and the resulting cell signaling cascade play a key role in metastasis and inflammation. On the basis of the previously published CXCR4 antagonist 5 (WZ811), a series of novel nonpeptidic anti-CXCR4 small molecules have been designed and synthesized to improve potency. Following a structure-activity profile around 5, more advanced compounds in the N,N'-(1, 4-phenylenebis(methylene)) dipyrimidin-2-amines series were discovered and shown to possess higher CXCR4 binding potential and specificity than 5. Compound 26 (508MCl) is the lead compound and exhibits subnanomolar potency in three in vitro assays including competitive binding, Matrigel invasion and Gα(i) cyclic adenosine monophosphate (cAMP) modulation signaling. Furthermore, compound 26 displays promising effects by interfering with CXCR4 function in three mouse models: paw inflammation, Matrigel plug angiogenesis, and uveal melanoma micrometastasis. These data demonstrate that dipyrimidine amines are unique CXCR4 antagonists with high potency and specificity.
authors.affiliation: Department of Radiology, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Aizhi
authors.initials: A
authors.lastname: Zhu
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Zhan
authors.forename: Zhongxing
authors.initials: Z
authors.lastname: Liang
authors.forename: Younghyoun
authors.initials: Y
authors.lastname: Yoon
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.forename: Hans E
authors.initials: HE
authors.lastname: Grossniklaus
authors.forename: Jianguo
authors.initials: J
authors.lastname: Xu
authors.forename: Mauricio
authors.initials: M
authors.lastname: Rojas
authors.forename: Mark
authors.initials: M
authors.lastname: Lockwood
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
authors.forename: Hyunsuk
authors.initials: H
authors.lastname: Shim
mesh_terms: D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D003094:Collagen; D004338:Drug Combinations; D005260:Female; D007249:Inflammation / Q000188:drug therapy; D007797:Laminin; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011509:Proteoglycans; D011658:Pulmonary Fibrosis / Q000188:drug therapy; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014604:Uveal Neoplasms / Q000188:drug therapy / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000098943:Uveal Melanoma
chemical_list: D000588:Amines; D020533:Angiogenesis Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; C514936:CXCR4 protein, mouse; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D011743:Pyrimidines; D019718:Receptors, CXCR4; C059485:matrigel; D003094:Collagen