SAR study on arylmethyloxyphenyl scaffold: Looking for a P-gp nanomolar affinity

• Development of novel arylmethyloxyphenyl derivatives as P-gp modulators.
• The effects in MDCK-MDR1 and MDCK-MRP1 cell lines were evaluated.
• P-gp inhibition potency is strongly related to the number of methoxy groups on A-ring.
• 10 is the most active compound displaying a nanomolar affinity towards P-gp.

Starting from the previously developed P-gp ligands 1a and 1b (EC50 = 0.25 μM and 0.65 μM, respectively), new arylmethyloxyphenyl derivatives have been synthesized as P-gp modulators in order to investigate: (i) the effect of small electron-donor groups (OMe) (5–11), (ii) the effect of the replacement of methoxy groups with an electron-withdrawal substituent (Cl) on C-ring (13) (iii) the effect induced by the replacement of C-ring with heteroaromatic cycles such as thiophene and pyrimidine (13, 15, 16), (iv) the effect induced by molecular constriction on C ring (14, 17, 18) on P-gp modulating activity. The results demonstrated that P-gp inhibition potency is strongly correlated to the number of methoxy groups in the A-ring whereas the methoxylation of C-ring seems to poorly affect P-gp activity. The best result was found for compound 10 that displays a nanomolar affinity (EC50 = 7.1 nM) towards P-gp pump and, in the meantime lacks of activity against MRP1 pump.

Figure optionsDownload as PowerPoint slide