Pyrimidine Ribonucleotides with Enhanced Selectivity as P2Y6 Receptor Agonists: Novel 4-Alkyloxyimino, (S)-Methanocarba, and 5′-Triphosphate γ-Ester Modificationsa

• Published in: Journal of medicinal chemistry Vol. 53; no. 11; pp. 4488 - 4501
• Main Authors: Maruoka, Hiroshi, Barrett, Matthew O., Ko, Hyojin, Tosh, Dilip K., Melman, Artem, Burianek, Lauren E., Balasubramanian, Ramachandran, Berk, Barkin, Costanzi, Stefano, Harden, T. Kendall, Jacobson, Kenneth A.
• Format: Journal Article
• Language: English
• Published: 10.06.2010
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm100287t

The P2Y 6 receptor is a cytoprotective G protein-coupled receptor (GPCR) activated by UDP (EC 50 , 0.30 μM). We compared and combined modifications to enhance P2Y 6 receptor agonist selectivity, including ribose ring constraint, 5-iodo and 4-alkyloxyimino modifications, and phosphate modifications such as α,β-methylene and extension of the terminal phosphate group into γ-esters of UTP analogues. The conformationally constrained (S)-methanocarba UDP is a full agonist (EC 50 0.042 μM). 4-Methoxyimino modification of pyrimidine enhanced P2Y 6 , preserved P2Y 2 and P2Y 4 , and abolished P2Y 14 receptor potency, in the appropriate nucleotide. N 4 -Benzyloxy-CDP ( 15 , MRS2964) and N 4 -methoxy-Cp 3 U ( 23 , MRS2957) were potent, selective P2Y 6 receptor agonists (EC 50 0.026 μM and 0.012 μM, respectively). A hydrophobic binding region near the nucleobase was explored with receptor modeling and docking. UTP-γ-aryl and cycloalkyl phosphoesters displayed only intermediate P2Y 6 receptor potency, but had enhanced stability in acid and cell membranes. UTP-glucose was inactive, but its (S)-methanocarba analogue and N 4 -methoxy-cytidine 5′-triphospho-γ-[1]glucose were active (EC 50 of 2.47 μM and 0.18 μM, respectively). Thus, the potency, selectivity, and stability of pyrimidine nucleotides as P2Y 6 receptor agonists may be enhanced by modest structural changes.