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.
Department of Medicinal Chemistry, Department of Pharmacology, Analytical Department, Xenova Ltd., 957 Buckingham Avenue, Slough, Berkshire SL1 4NL,UK. swang@trigen.co.uk
Shouming
S
Wang
Nan Chi
NC
Wan
John
J
Harrison
Warren
W
Miller
Irina
I
Chuckowree
Sukhjit
S
Sohal
Timothy C
TC
Hancox
Stewart
S
Baker
Adrian
A
Folkes
Francis
F
Wilson
Deanne
D
Thompson
Simon
S
Cocks
Hayley
H
Farmer
Anthony
A
Boyce
Caroline
C
Freathy
Jan
J
Broadbridge
John
J
Scott
Paul
P
Depledge
Richard
R
Faint
Prakash
P
Mistry
Peter
P
Charlton
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