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

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. Copyright © 2014. Published by Elsevier Masson SAS.

Citation

Giulia Nesi, Nicola Antonio Colabufo, Marialessandra Contino, Maria Grazia Perrone, Maria Digiacomo, Roberto Perrone, Annalina Lapucci, Marco Macchia, Simona Rapposelli. SAR study on arylmethyloxyphenyl scaffold: looking for a P-gp nanomolar affinity. European journal of medicinal chemistry. 2014 Apr 9;76:558-66

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PMID: 24607999

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