Applying the pro-drug approach to afford highly bioavailable antagonists of P2Y14

A Selective High-Affinity Antagonist of the P2Y14 Receptor Inhibits UDP-Glucose–Stimulated Chemotaxis of Human Neutrophils

“…High-affinity competitive antagonists were developed for the P2Y 1 -R, and both competitive and noncompetitive antagonists are available for the P2Y 12 -R. However, such highly selective probes have not been available for the other subtypes of P2Y-R, and thus, the work of Black and colleagues, recently identifying potential antagonist molecules for the P2Y 14 -R, is promising Guay et al, 2011;Robichaud et al, 2011). High-throughput screens measuring small molecule-dependent inhibition of UDP-glucose-stimulated Ca 21 mobilization in P2Y 14 -R-expressing HEK cells identified dihydropyridopyrimidine (Guay et al, 2011) and naphthoic acid-containing molecules as potential P2Y 14 -R inhibitors.…”

“…It was concluded on the basis of lack of inhibition of [ 3 H]UDP binding that the dihydropyridopyrimidine derivatives were noncompetitive inhibitors of the P2Y 14 -R (Guay et al, 2011). Conversely, several of the naphthoic acid derivatives, including PPTN, inhibited [ 3 H]UDP binding with apparent binding affinities in the low nanomolar range of concentrations Robichaud et al, 2011). Of interest, one of the highest apparent affinity naphthoic acid derivatives also bound with high affinity to serum proteins, and therefore, PPTN was identified as a naphthoic acid derivative that bound with high apparent affinity to the P2Y 14 -R but exhibited less robust human serum albumin binding (Robichaud et al, 2011).…”

“…Conversely, several of the naphthoic acid derivatives, including PPTN, inhibited [ 3 H]UDP binding with apparent binding affinities in the low nanomolar range of concentrations Robichaud et al, 2011). Of interest, one of the highest apparent affinity naphthoic acid derivatives also bound with high affinity to serum proteins, and therefore, PPTN was identified as a naphthoic acid derivative that bound with high apparent affinity to the P2Y 14 -R but exhibited less robust human serum albumin binding (Robichaud et al, 2011). A prodrug derivative of PPTN (an ester of the carboxylic acid) also was prepared to enhance its bioavailability.…”

“…Availability of a receptor-selective antagonist for the P2Y 14 -R receptor is crucial for elucidation of the role(s) played by this signaling protein in inflammatory/immune responses. To this end, two classes of molecules recently were found by Black and colleagues to act as antagonists of the P2Y 14 -R, and these hits were structurally modified to enhance receptor affinity Guay et al, 2011;Robichaud et al, 2011). We now have studied one of these optimized compounds in detail.…”

UDP-Sugars as Extracellular Signaling Molecules: Cellular and Physiologic Consequences of P2Y14 Receptor Activation

“…Black and coworkers applied high-throughput screens to identify dihydropyridopyrimidine (Guay et al, 2011) and naphthoic acid Robichaud et al, 2011). Problems with high-affinity binding to serum proteins observed with several of these naphthoic acid analogs were partially circumvented in the analog PPTN [4-((piperidin-4-yl)-phenyl)-7-(4-(trifluoromethyl)-phenyl)-2-naphthoic acid] that retained activity as a P2Y 14 R antagonist.…”