Synthesis of a new inhibitor of breast cancer resistance protein with significantly improved pharmacokinetic profiles

[Display omitted] The design, synthesis, in vitro inhibitory potency, and pharmacokinetic (PK) profiles of Ko143 analogs are described. Compared to commonly used Ko143, the new breast cancer resistance protein (BCRP) inhibitor (compound A) showed the same potency and a significantly improved PK prof...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2016-01, Vol.26 (2), p.551-555
Main Authors: Li, Yuexian, Woo, Jiyeon, Chmielecki, Jessica, Xia, Cindy Q., Liao, Mingxiang, Chuang, Bei-Ching, Yang, Johnny J., Guan, Miao Y., Plesescu, Mihaela, Prakash, Shimoga R.
Format: Article
Language:English
Subjects:
Animals
ATP Binding Cassette Transporter, Sub-Family G, Member 2 - antagonists & inhibitors
ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors
BCRP
Caco-2 Cells
Compound A
Diketopiperazines - chemical synthesis
Diketopiperazines - pharmacokinetics
Estrone - analogs & derivatives
Estrone - metabolism
Heterocyclic Compounds, 4 or More Rings - blood
Heterocyclic Compounds, 4 or More Rings - chemical synthesis
Heterocyclic Compounds, 4 or More Rings - pharmacokinetics
Humans
Inhibitors
Ko134
Ko143
PK profiles
Rats
Stereoisomerism
Structure-Activity Relationship
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Description
Summary:[Display omitted] The design, synthesis, in vitro inhibitory potency, and pharmacokinetic (PK) profiles of Ko143 analogs are described. Compared to commonly used Ko143, the new breast cancer resistance protein (BCRP) inhibitor (compound A) showed the same potency and a significantly improved PK profile in rats (lower clearance [1.54L/h/kg] and higher bioavailability [123%]). Ko143 on the other hand suffers from poor bioavailability. Compared to Ko143, compound A would be a useful probe for delineating the role of BCRP during in vivo studies in animals.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2015.11.077