SAR Studies on Tetrahydroisoquinoline Derivatives: The Role of Flexibility and Bioisosterism To Raise Potency and Selectivity toward P-glycoproteinCapparelli, E., Zinzi, L., Cantore, M., Contino, M., Perrone, M. G., Luurtsema, G., Berardi, F., Perrone, R. & Colabufo, N. A., 11-Dec-2014, In : Journal of Medicinal Chemistry. 57, 23, p. 9983-9994 12 p.
Research output: Contribution to journal › Article › Academic › peer-review
The development of P-glycoprotein (P-gp) ligands remains of considerable interest, mostly for investigating the protein's structure and transport mechanism. In recent years, many different generations of ligands have been tested for their ability to modulate P-gp activity. The aim of the present work is to perform SAR studies on tetrahydroisoquinoline derivatives in order to design potent and selective P-gp ligands. For this purpose, the effect of bioisosteric replacement and the role of flexibility have been investigated, and four series of tetrahydroisoquinoline ligands have been developed: (a) 2-aryloxazole bioisosteres, (b) elongated analogues, (c) 2H-chromene, and (d) 2-biphenyl derivatives. The results showed that both 2-biphenyl derivative 20b and elongated derivative 6g behaved as strong P-gp substrates. In conclusion, important aspects for developing potent and selective P-gp ligands have been highlighted, providing a solid starting point for further optimization.
|Number of pages||12|
|Journal||Journal of Medicinal Chemistry|
|Publication status||Published - 11-Dec-2014|
- BLOOD-BRAIN-BARRIER, MULTIDRUG-RESISTANCE, PRECLINICAL EVALUATION, DRUG-BINDING, IN-VIVO, CANCER, PET, EXPRESSION, MODULATORS, INHIBITORS