SAR studies on tetrahydroisoquinoline derivatives: the role of flexibility and bioisosterism to raise potency and selectivity on P-gp protein.

The development of P-glycoprotein (P-gp) ligands remains of considerable interest mostly for investigating protein structure and transport mechanism. In the last years many ligands, belonging to different generations, have been tested for modulating P-gp activity. 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-aryoxazole bioisosteres; b) elongated analogues; c) 2H-Chromene and d) 2-biphenyl derivatives. Obtained results showed that both 2-biphenyl derivative 20b and elongated derivative 6g behaved as strong P-gp substrates. In conclusion important items have been highlighted for developing potent and selective P-gp ligands providing a solid starting point for further optimization.