SAR studies on tetrahydroisoquinoline derivatives: the role of flexibility and bioisosterism to raise potency and selectivity toward P-glycoprotein.
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.
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "A. Moro" , via Orabona 4, 70125 Bari, Italy.
Elena
E
Capparelli
Laura
L
Zinzi
Mariangela
M
Cantore
Marialessandra
M
Contino
Maria Grazia
MG
Perrone
Gert
G
Luurtsema
Francesco
F
Berardi
Roberto
R
Perrone
Nicola A
NA
Colabufo
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D004285:Dogs; D005452:Fluoresceins / Q000378:metabolism; D008024:Ligands; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000737:chemistry
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001713:Biphenyl Compounds; D005452:Fluoresceins; D008024:Ligands; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D044005:Tetrahydroisoquinolines; C579243:6,7-dimethoxy-2-(4-methoxybiphenyl-4-yl-methyl)-1,2,3,4-tetrahydroisoquinoline; C085925:calcein AM; C010574:biphenyl; C421109:multidrug resistance-associated protein 1