Studies on pyrrolopyrimidines as selective inhibitors of multidrug-resistance-associated protein in multidrug resistance.
Multidrug resistance mediated by P-glycoprotein (Pgp) or multidrug-resistance-associated protein (MRP) remains a major obstacle for successful treatment of cancer. Inhibition of Pgp and MRP transport is important for high efficacy of anticancer drugs. While several Pgp inhibitors have entered clinical trials, the development of specific MRP1 inhibitors is still in its infancy. In our screening program, we have identified a pyrrolopyrimidine (4) as a novel and selective MRP1 inhibitor. Subsequent SAR work on the 4-position of the template revealed the phenethylpiperazine side chain as a potent replacement of the benzylthio group of the lead molecule. Introduction of groups at the 2-position seems to have no detrimental effect on activity. Modifications to the nitrile group at the 7-position resulted in the identification of analogues with groups, such as amides, with superior pharmacokinetic profiles. In vivo efficacy has been demonstrated by xenograft studies on selected compounds.
Department of Medicinal Chemistry, Department of Pharmacology, and Analytical Department, Xenova Ltd., 957 Buckingham Avenue, Slough, Berkshire SL1 4NL, U.K. swang@trigen.co.uk
Shouming
S
Wang
Adrian
A
Folkes
Irina
I
Chuckowree
Xiaoling
X
Cockcroft
Sukhjit
S
Sohal
Warren
W
Miller
John
J
Milton
Stephen P
SP
Wren
Nigel
N
Vicker
Paul
P
Depledge
John
J
Scott
Lyndsay
L
Smith
Hazel
H
Jones
Prakash
P
Mistry
Richard
R
Faint
Deanne
D
Thompson
Simon
S
Cocks
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001692:Biological Transport; D045744:Cell Line, Tumor; D020650:Combinatorial Chemistry Techniques; D003630:Daunorubicin / Q000378:metabolism / 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; 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; D003630:Daunorubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011743:Pyrimidines; D011758:Pyrroles