Design and synthesis of new templates derived from pyrrolopyrimidine as selective multidrug-resistance-associated protein inhibitors in multidrug resistance.
In our continued effort to identify selective MRP1 modulators, we have developed two novel templates, 3 and 4, through rational drug design by identifying the key pharmacophore interaction at the 7-position of the pyrrolopyrimidine template 1. Further synthesis and SAR work on these novel templates gave a number of potent MRP1 modulators with great selectivity against Pgp. Additional studies to reduce the CYP3A4 inhibition are also reported. Several compounds of these classes were subjected to in vivo xenograft studies and in vivo efficacies were demonstrated.
Wang
Shouming
S
Department of Medicinal Chemistry, Department of Pharmacology, Analytical Department, Xenova Ltd., 957 Buckingham Avenue, Slough, Berkshire SL1 4NL,UK. swang@trigen.co.uk
Wan
Nan Chi
NC
Harrison
John
J
Miller
Warren
W
Chuckowree
Irina
I
Sohal
Sukhjit
S
Hancox
Timothy C
TC
Baker
Stewart
S
Folkes
Adrian
A
Wilson
Francis
F
Thompson
Deanne
D
Cocks
Simon
S
Farmer
Hayley
H
Boyce
Anthony
A
Freathy
Caroline
C
Broadbridge
Jan
J
Scott
John
J
Depledge
Paul
P
Faint
Richard
R
Mistry
Prakash
P
Charlton
Peter
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D045744:Cell Line, Tumor; D020650:Combinatorial Chemistry Techniques; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D004357:Drug Synergism; D005260:Female; D006207:Half-Life; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004317:Doxorubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011743:Pyrimidines; D011758:Pyrroles; C104464:CYP3A protein, human; C510163:CYP3A4 protein, human