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

Yuexian Li; Jiyeon Woo; Jessica Chmielecki; Cindy Q Xia; Mingxiang Liao; Bei-Ching Chuang; Johnny J Yang; Miao Y Guan; Mihaela Plesescu; Shimoga R Prakash

doi:10.1016/j.bmcl.2015.11.077

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

Bioorg Med Chem Lett. 2016 Jan 15;26(2):551-555. doi: 10.1016/j.bmcl.2015.11.077. Epub 2015 Nov 22.

Authors

Affiliations

¹ Department of Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., 35 Landsdowne Street, Cambridge, MA 02139, USA. Electronic address: [email protected].
² Boston University, 881 Commonwealth Avenue, Boston, MA 02215, USA.
³ Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
⁴ Department of Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., 35 Landsdowne Street, Cambridge, MA 02139, USA.

PMID: 26642765
DOI: 10.1016/j.bmcl.2015.11.077

Abstract

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.

Keywords: BCRP; Compound A; Inhibitors; Ko134; Ko143; PK profiles.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
ATP Binding Cassette Transporter, Subfamily G, Member 2 / antagonists & inhibitors*
Animals
Caco-2 Cells
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
Rats
Stereoisomerism
Structure-Activity Relationship

Substances

3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester
6-isobutyl-9-methoxy-3-methyl-2,3,6,7,12,12a-hexahydropyrazino(1',2'-1,6)pyrido(3,4-b)indole-1,4-dione
ATP Binding Cassette Transporter, Subfamily B, Member 1
ATP Binding Cassette Transporter, Subfamily G, Member 2
Abcg2 protein, mouse
Diketopiperazines
Heterocyclic Compounds, 4 or More Rings
Estrone
estrone sulfate