Abstract
P2Y(6) receptor (P2Y(6)R) antagonists represent potential drugs for treating cancer, pain, neurodegeneration, asthma, diabetes, colitis and other disorders. However, there are few chemical classes of known competitive antagonists. We recently explored the structure activity relationship (SAR) of 2H-chromene derivatives as P2Y(6)R antagonists of moderate affinity. New analogues in this series modified at five positions were synthesized and shown to antagonize Ca(2+) transients induced by the native agonist UDP in human (h) P2Y(6)R-expressing (but not turkey P2Y(1)R-, hP2Y(2)R- or hP2Y(4)R-expressing) astrocytoma cells. Alternatives to the reported 2-(trifluoromethyl)- and 3-nitro- substitutions of this scaffold were not identified. However, 6‑fluoro 11 and 6‑chloro 12 analogues displayed enhanced potency compared to other halogens, although still in the 1 - 2 µM range. Similar halogen substitution at 5, 7 or 8 positions reduced affinity. 5- or 8‑Triethylsilylethynyl extension maintained hP2Y(6)R affinity, with IC(50) 0.46 µM for 26 (MRS4853). The 6,8‑difluoro analogue 27 (IC(50) 2.99 µM) lacked off-target activities among 45 sites examined, unlike earlier analogues that bound to biogenic amine receptors. 11 displayed only one weak off-target activity (σ(2)). Mouse P2Y(6)R IC(50)s of 5, 25, 26 and 27 were 4.94, 17.6, 6.15 and 17.8 µM, respectively, but most other analogues had reduced affinity (>20 µM) compared to the hP2Y(6)R. These analogues are suitable for evaluation in in vivo inflammation and cancer models, which will be performed in the future studies.