Azoheteroarene-Modified Grapiprants Serving as Photoswitchable EP4 Antagonists

Published in: Chemistry – A European Journal

DOI: 10.1002/chem.202503349

Authors: Md. Akram Ali [TCGLS Member], Satyajit Bera, Rajib Chakraborty [TCGLS Member], Susanta Kumar Mondal [TCGLS Member], SupriyaBhunia, Tapas Sardar [TCGLS Member], Sabyasachi Chakraborty, Subhas Samanta

ABSTRACT

Photopharmacology offers a novel approach to eliminate side effects of chemotherapy treatment via site-specific activation of light-active anticancer agents, which are typically constructed by the installation of light-cleavable or light-switchable molecules onto known drugs or inhibitors. The light-switchable drugs being able to reversibly control biological activities are more advantageous, but the design of such compounds is very challenging. We synthesized a small series of photoswitchable S-arylsulfonylurea-based EP4 antagonists by substituting a core structural unit of a potent EP4 antagonist, grapiprant. In vitro cell-based EP4 activity studies revealed that all light-induced cis isomers of these compounds are more potent than their trans isomers. Compound 3, with an azopyrazolephotoswitch and a para-methyl substitution in the S-phenyl ring, displayed the highest EP4 antagonism by its cis isomer and a considerably larger activity difference (ca. 1.8-fold) between trans and cis photoisomers. It showed (near) complete photoisomerization (∼95%–98%) upon 365 nm (forward) and 520 nm (reverse) light irradiations. The metastable cis isomers demonstrated high thermal stability (t_1/2 = 1–3 days). All compounds were resistant to photobleaching and showed impressive stability for reduction with glutathione (10 mM). This study constitutes a proof-of-concept to design photoswitchable EP4 antagonists, and the structure-activity relationship revealed herein may help design more potent grapiprant derivatives.

Graphical Abstract

Modification of the anti-inflammatory drug grapiprant by azoheteroarenes renders it a reversibly light-controllable EP4 antagonist. In vitro cell-based EP4 activity studies revealed that the cis isomer of the lead antagonist, which relatively strongly binds with the EP4 receptor involving its compact T-shaped geometry, was 1.8-fold more potent than its trans isomer.