伪,尾-Methylene-ADP (AOPCP) Derivatives and Analogues: Development of Potent and Selective ecto-5鈥?Nucleotidase (CD73) Inhibitors

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• 作者：Sanjay Bhattarai ; Marianne Freundlieb ; Jan Pippel ; Anne Meyer ; Aliaa Abdelrahman ; Amelie Fiene ; Sang-Yong Lee ; Herbert Zimmermann ; Gennady G. Yegutkin ; Norbert Str盲ter ; Ali El-Tayeb ; Christa E. M眉ller
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：August 13, 2015
• 年：2015
• 卷：58
• 期：15
• 页码：6248-6263
• 全文大小：734K
• ISSN：1520-4804

文摘

ecto-5鈥?Nucleotidase (eN, CD73) catalyzes the hydrolysis of extracellular AMP to adenosine. eN inhibitors have potential for use as cancer therapeutics. The eN inhibitor 伪,尾-methylene-ADP (AOPCP, adenosine-5鈥?O-[(phosphonomethyl)phosphonic acid]) was used as a lead structure, and derivatives modified in various positions were prepared. Products were tested at rat recombinant eN. 6-(Ar)alkylamino substitution led to the largest improvement in potency. N⁶-Monosubstitution was superior to symmetrical N⁶,N⁶-disubstitution. The most potent inhibitors were N⁶-(4-chlorobenzyl)- (10l, PSB-12441, K_i 7.23 nM), N⁶-phenylethyl- (10h, PSB-12425, K_i 8.04 nM), and N⁶-benzyl-adenosine-5鈥?O-[(phosphonomethyl)phosphonic acid] (10g, PSB-12379, K_i 9.03 nM). Replacement of the 6-NH group in 10g by O (10q, PSB-12431) or S (10r, PSB-12553) yielded equally potent inhibitors (10q, 9.20 nM; 10r, 9.50 nM). Selected compounds investigated at the human enzyme did not show species differences; they displayed high selectivity versus other ecto-nucleotidases and ADP-activated P2Y receptors. Moreover, high metabolic stability was observed. These compounds represent the most potent eN inhibitors described to date.