title: Synthesis of a new inhibitor of breast cancer resistance protein with significantly improved pharmacokinetic profiles.
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.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., 35 Landsdowne Street, Cambridge, MA 02139, USA. Electronic address: yuexianfrank.li@takeda.com.
authors.forename: Yuexian
authors.initials: Y
authors.lastname: Li
authors.affiliation: Boston University, 881 Commonwealth Avenue, Boston, MA 02215, USA.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Woo
authors.affiliation: Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Chmielecki
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., 35 Landsdowne Street, Cambridge, MA 02139, USA.
authors.forename: Cindy Q
authors.initials: CQ
authors.lastname: Xia
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., 35 Landsdowne Street, Cambridge, MA 02139, USA.
authors.forename: Mingxiang
authors.initials: M
authors.lastname: Liao
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., 35 Landsdowne Street, Cambridge, MA 02139, USA.
authors.forename: Bei-Ching
authors.initials: BC
authors.lastname: Chuang
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., 35 Landsdowne Street, Cambridge, MA 02139, USA.
authors.forename: Johnny J
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., 35 Landsdowne Street, Cambridge, MA 02139, USA.
authors.forename: Miao Y
authors.initials: MY
authors.lastname: Guan
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., 35 Landsdowne Street, Cambridge, MA 02139, USA.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Plesescu
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., 35 Landsdowne Street, Cambridge, MA 02139, USA.
authors.forename: Shimoga R
authors.initials: SR
authors.lastname: Prakash
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000037:antagonists & inhibitors*; D000818:Animals; D018938:Caco-2 Cells; D054659:Diketopiperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D006801:Humans; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C541506:3-(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; C000613479:6-isobutyl-9-methoxy-3-methyl-2,3,6,7,12,12a-hexahydropyrazino(1',2'-1,6)pyrido(3,4-b)indole-1,4-dione; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; C501412:Abcg2 protein, mouse; D054659:Diketopiperazines; D006576:Heterocyclic Compounds, 4 or More Rings; D004970:Estrone; C017296:estrone sulfate
keywords: BCRP; Compound A; Inhibitors; Ko134; Ko143; PK profiles