DeMarco Steven J, Henze Heiko, Lederer Alexander, Moehle Kerstin, Mukherjee Reshmi, Romagnoli Barbara, Robinson John A, Brianza Federico, Gombert Frank O, Lociuro Sergio, Ludin Christian, Vrijbloed Jan Willem, Zumbrunn Jürg, Obrecht Jean-Pierre, Obrecht Daniel, Brondani Vincent, Hamy François, Klimkait Thomas
Chemistry Department, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
Bioorg Med Chem. 2006 Dec 15;14(24):8396-404. doi: 10.1016/j.bmc.2006.09.003. Epub 2006 Sep 28.
Novel highly potent CXCR4 inhibitors with good pharmacokinetic properties were designed and optimized starting from the naturally occurring beta-hairpin peptide polyphemusin II. The design involved incorporating important residues from polyphemusin II into a macrocyclic template-bound beta-hairpin mimetic. Using a parallel synthesis approach, the potency and ADME properties of the mimetics were optimized in iterative cycles, resulting in the CXCR4 inhibitors POL2438 and POL3026. The inhibitory potencies of these compounds were confirmed in a series of HIV-1 invasion assays in vitro. POL3026 showed excellent plasma stability, high selectivity for CXCR4, favorable pharmacokinetic properties in the dog, and thus has the potential to become a therapeutic compound for application in the treatment of HIV infections (as an entry inhibitor), cancer (for angiogenesis suppression and inhibition of metastasis), inflammation, and in stem cell transplant therapy.
以天然存在的β-发夹肽海兔毒素II为起始原料，设计并优化了具有良好药代动力学性质的新型高效CXCR4抑制剂。该设计包括将海兔毒素II的重要残基整合到与大环模板结合的β-发夹模拟物中。采用平行合成方法，通过迭代循环优化模拟物的活性和药物代谢及药代动力学性质，得到了CXCR4抑制剂POL2438和POL3026。这些化合物的抑制活性在一系列体外HIV-1入侵试验中得到了证实。POL3026表现出优异的血浆稳定性、对CXCR4的高选择性、在犬体内良好的药代动力学性质，因此有潜力成为一种治疗化合物，用于治疗HIV感染（作为进入抑制剂）、癌症（用于抑制血管生成和转移）、炎症以及干细胞移植治疗。
