A1 Refereed original research article in a scientific journal

alpha,beta-Methylene-ADP (AOPCP) Derivatives and Analogues: Development of Potent and Selective ecto-5 '-Nucleotidase (CD73) Inhibitors




AuthorsBhattarai S, Freundlieb M, Pippel J, Meyer A, Abdelrahman A, Fiene A, Lee SY, Zimmermann H, Yegutkin GG, Strater N, El-Tayeb A, Muller CE

PublisherAMER CHEMICAL SOC

Publication year2015

JournalJournal of Medicinal Chemistry

Journal name in sourceJOURNAL OF MEDICINAL CHEMISTRY

Journal acronymJ MED CHEM

Volume58

Issue15

First page 6248

Last page6263

Number of pages16

ISSN0022-2623

DOIhttps://doi.org/10.1021/acs.jmedchem.5b00802(external)


Abstract

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 alpha,beta-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-(4chlorobenzyl)-(10l, PSB-12441, K-i 7.23 n.M), 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 0 (10q, PSB-12431) or S (10r, PSB-12553) yielded equally potent inhibitors (10q, 9.20 nM; 10r, 9.50 aM). Selected compounds investigated at the human enzyme did not show species differences; they displayed high selectivity versus other ecto-nudeotidases and ADP-activated P2Y receptors. Moreover, high metabolic stability was observed. These compounds represent the most potent eN inhibitors described to date.




Last updated on 2024-26-11 at 21:06