SAR study on arylmethyloxyphenyl scaffold: looking for a P-gp nanomolar affinity.
Eur J Med Chem
; 76: 558-66, 2014 Apr 09.
Article
in En
| MEDLINE
| ID: mdl-24607999
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
ATP Binding Cassette Transporter, Subfamily B, Member 1
Limits:
Humans
Language:
En
Journal:
Eur J Med Chem
Year:
2014
Document type:
Article
Affiliation country:
Italy