α,β-Methylene-ADP (AOPCP) Derivatives and Analogues: Development of Potent and Selective ecto-5′-Nucleotidase (CD73) Inhibitors

ecto-5′-Nucleotidase (eN, CD73) catalyzes the hydrolysis of extracellular AMP to adenosine. eN inhibitors have potential for use as cancer therapeutics. The eN inhibitor α,β-methylene-ADP (AOPCP, adenosine-5′-O-[(phosphonomethyl)­phosphonic acid]) was used as a lead structure, and derivatives modifi...

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Published in:Journal of medicinal chemistry 2015-08, Vol.58 (15), p.6248-6263
Main Authors: Bhattarai, Sanjay, Freundlieb, Marianne, Pippel, Jan, Meyer, Anne, Abdelrahman, Aliaa, Fiene, Amelie, Lee, Sang-Yong, Zimmermann, Herbert, Yegutkin, Gennady G, Sträter, Norbert, El-Tayeb, Ali, Müller, Christa E
Format: Article
Language:English
Subjects:
5'-Nucleotidase - antagonists & inhibitors
Adenosine Diphosphate - analogs & derivatives
Adenosine Diphosphate - chemistry
Adenosine Diphosphate - pharmacology
Animals
Cell Line
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Humans
Microsomes, Liver - drug effects
Models, Molecular
Rats
Spodoptera
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Summary:ecto-5′-Nucleotidase (eN, CD73) catalyzes the hydrolysis of extracellular AMP to adenosine. eN inhibitors have potential for use as cancer therapeutics. The eN inhibitor α,β-methylene-ADP (AOPCP, adenosine-5′-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. N 6-Monosubstitution was superior to symmetrical N 6,N 6-disubstitution. The most potent inhibitors were N 6-(4-chlorobenzyl)- (10l, PSB-12441, K i 7.23 nM), N 6-phenylethyl- (10h, PSB-12425, K i 8.04 nM), and N 6-benzyl-adenosine-5′-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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.5b00802