title: Discovery and characterization of novel inhibitors of the sodium-coupled citrate transporter (NaCT or SLC13A5).
abstract: Citrate is a key regulatory metabolic intermediate as it facilitates the integration of the glycolysis and lipid synthesis pathways. Inhibition of hepatic extracellular citrate uptake, by blocking the sodium-coupled citrate transporter (NaCT or SLC13A5), has been suggested as a potential therapeutic approach to treat metabolic disorders. NaCT transports citrate from the blood into the cell coupled to the transport of sodium ions. The studies herein report the identification and characterization of a novel small dicarboxylate molecule (compound 2) capable of selectively and potently inhibiting citrate transport through NaCT, both in vitro and in vivo. Binding and transport experiments indicate that 2 specifically binds NaCT in a competitive and stereosensitive manner, and is recognized as a substrate for transport by NaCT. The favorable pharmacokinetic properties of 2 permitted in vivo experiments to evaluate the effect of inhibiting hepatic citrate uptake on metabolic endpoints.
authors.affiliation: Worldwide Medicinal Chemistry, 610 Main street, Cambridge, MA 02139.
authors.forename: Kim
authors.initials: K
authors.lastname: Huard
authors.affiliation: Pharmacokinetics, Dynamics, and Metabolism, Eastern Point road, Groton, CT 06340.
authors.forename: Janice
authors.initials: J
authors.lastname: Brown
authors.affiliation: Cardiovascular, Metabolic &Endocrine Disease Research Unit, 610 Main street, Cambridge, MA 02139.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Jones
authors.affiliation: Worldwide Medicinal Chemistry, Eastern Point road, Groton, CT 06340.
authors.forename: Shawn
authors.initials: S
authors.lastname: Cabral
authors.affiliation: Worldwide Medicinal Chemistry, 610 Main street, Cambridge, MA 02139.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Futatsugi
authors.affiliation: Cardiovascular, Metabolic &Endocrine Disease Research Unit, 610 Main street, Cambridge, MA 02139.
authors.forename: Matthew
authors.initials: M
authors.lastname: Gorgoglione
authors.affiliation: Cardiovascular, Metabolic &Endocrine Disease Research Unit, 610 Main street, Cambridge, MA 02139.
authors.forename: Adhiraj
authors.initials: A
authors.lastname: Lanba
authors.affiliation: Cardiovascular, Metabolic &Endocrine Disease Research Unit, 610 Main street, Cambridge, MA 02139.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Vera
authors.affiliation: Cardiovascular, Metabolic &Endocrine Disease Research Unit, 610 Main street, Cambridge, MA 02139.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Cardiovascular, Metabolic &Endocrine Disease Research Unit, 610 Main street, Cambridge, MA 02139.
authors.forename: Qingyun
authors.initials: Q
authors.lastname: Yan
authors.affiliation: Cardiovascular, Metabolic &Endocrine Disease Research Unit, 610 Main street, Cambridge, MA 02139.
authors.forename: Yingjiang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Cardiovascular, Metabolic &Endocrine Disease Research Unit, 610 Main street, Cambridge, MA 02139.
authors.forename: Cecile
authors.initials: C
authors.lastname: Vernochet
authors.affiliation: Pharmacokinetics, Dynamics, and Metabolism, Eastern Point road, Groton, CT 06340.
authors.forename: Keith
authors.initials: K
authors.lastname: Riccardi
authors.affiliation: Pharmacokinetics, Dynamics, and Metabolism, Eastern Point road, Groton, CT 06340.
authors.forename: Angela
authors.initials: A
authors.lastname: Wolford
authors.affiliation: Pharmacokinetics, Dynamics, and Metabolism, Eastern Point road, Groton, CT 06340.
authors.forename: David
authors.initials: D
authors.lastname: Pirman
authors.affiliation: Pharmacokinetics, Dynamics, and Metabolism, Eastern Point road, Groton, CT 06340.
authors.forename: Mark
authors.initials: M
authors.lastname: Niosi
authors.affiliation: Worldwide Medicinal Chemistry, 610 Main street, Cambridge, MA 02139.
authors.forename: Gary
authors.initials: G
authors.lastname: Aspnes
authors.affiliation: Worldwide Medicinal Chemistry, Eastern Point road, Groton, CT 06340.
authors.forename: Michael
authors.initials: M
authors.lastname: Herr
authors.affiliation: Worldwide Medicinal Chemistry, Eastern Point road, Groton, CT 06340.
authors.forename: Nathan E
authors.initials: NE
authors.lastname: Genung
authors.affiliation: Worldwide Medicinal Chemistry, 610 Main street, Cambridge, MA 02139.
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Magee
authors.affiliation: Worldwide Medicinal Chemistry, Eastern Point road, Groton, CT 06340.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Uccello
authors.affiliation: Pharmacokinetics, Dynamics, and Metabolism, Eastern Point road, Groton, CT 06340.
authors.forename: Paula
authors.initials: P
authors.lastname: Loria
authors.affiliation: Pharmacokinetics, Dynamics, and Metabolism, Eastern Point road, Groton, CT 06340.
authors.forename: Li
authors.initials: L
authors.lastname: Di
authors.affiliation: Pharmacokinetics, Dynamics, and Metabolism, 610 Main street, Cambridge, MA 02139.
authors.forename: James R
authors.initials: JR
authors.lastname: Gosset
authors.affiliation: Worldwide Medicinal Chemistry, 610 Main street, Cambridge, MA 02139.
authors.forename: David
authors.initials: D
authors.lastname: Hepworth
authors.affiliation: Cardiovascular, Metabolic &Endocrine Disease Research Unit, 610 Main street, Cambridge, MA 02139.
authors.forename: Timothy
authors.initials: T
authors.lastname: Rolph
authors.affiliation: Cardiovascular, Metabolic &Endocrine Disease Research Unit, 610 Main street, Cambridge, MA 02139.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Pfefferkorn
authors.affiliation: Cardiovascular, Metabolic &Endocrine Disease Research Unit, 610 Main street, Cambridge, MA 02139.
authors.forename: Derek M
authors.initials: DM
authors.lastname: Erion
mesh_terms: D019343:Citric Acid / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D027981:Symporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C470492:SLC13A5 protein, human; D027981:Symporters; D019343:Citric Acid