Optimization of a Dicarboxylic Series for in Vivo Inhibition of Citrate Transport by the Solute Carrier 13 (SLC13) Family

Kim Huard; James R Gosset; Justin I Montgomery; Adam Gilbert; Matthew M Hayward; Thomas V Magee; Shawn Cabral; Daniel P Uccello; Kevin Bahnck; Janice Brown; Julie Purkal; Matthew Gorgoglione; Adhiraj Lanba; Kentaro Futatsugi; Michael Herr; Nathan E Genung; Gary Aspnes; Jana Polivkova; Carmen N Garcia-Irizarry; Qifang Li; Daniel Canterbury; Mark Niosi; Nicholas B Vera; Zhenhong Li; Bhagyashree Khunte; Jaclyn Siderewicz; Timothy Rolph; Derek M Erion

doi:10.1021/acs.jmedchem.5b01752

Optimization of a Dicarboxylic Series for in Vivo Inhibition of Citrate Transport by the Solute Carrier 13 (SLC13) Family

J Med Chem. 2016 Feb 11;59(3):1165-75. doi: 10.1021/acs.jmedchem.5b01752. Epub 2016 Jan 27.

Authors

Kim Huard^{1

2}, James R Gosset^{1

2}, Justin I Montgomery^{1

2}, Adam Gilbert^{1

2}, Matthew M Hayward^{1

2}, Thomas V Magee^{1

2}, Shawn Cabral^{1

2}, Daniel P Uccello^{1

2}, Kevin Bahnck^{1

2}, Janice Brown^{1

2}, Julie Purkal^{1

2}, Matthew Gorgoglione^{1

2}, Adhiraj Lanba^{1

2}, Kentaro Futatsugi^{1

2}, Michael Herr^{1

2}, Nathan E Genung^{1

2}, Gary Aspnes^{1

2}, Jana Polivkova^{1

2}, Carmen N Garcia-Irizarry^{1

2}, Qifang Li^{1

2}, Daniel Canterbury^{1

2}, Mark Niosi^{1

2}, Nicholas B Vera^{1

2}, Zhenhong Li^{1

2}, Bhagyashree Khunte^{1

2}, Jaclyn Siderewicz^{1

2}, Timothy Rolph^{1

2}, Derek M Erion^{1

2}

Affiliations

¹ Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.
² Worldwide Medicinal Chemistry, and ⊥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.

PMID: 26734723
DOI: 10.1021/acs.jmedchem.5b01752

Abstract

Inhibition of the sodium-coupled citrate transporter (NaCT or SLC13A5) has been proposed as a new therapeutic approach for prevention and treatment of metabolic diseases. In a previous report, we discovered dicarboxylate 1a (PF-06649298) which inhibits the transport of citrate in in vitro and in vivo settings via a specific interaction with NaCT. Herein, we report the optimization of this series leading to 4a (PF-06761281), a more potent inhibitor with suitable in vivo pharmacokinetic profile for assessment of in vivo pharmacodynamics. Compound 4a was used to demonstrate dose-dependent inhibition of radioactive [(14)C]citrate uptake in liver and kidney in vivo, resulting in modest reductions in plasma glucose concentrations.

MeSH terms

Animals
Biological Transport / drug effects
Blood Glucose / metabolism
Citrates / metabolism*
Citrates / pharmacokinetics
Dose-Response Relationship, Drug
HEK293 Cells
Hepatocytes / drug effects
Humans
Kidney / drug effects
Kidney / metabolism
Liver / drug effects
Liver / metabolism
Malates / administration & dosage
Malates / chemistry*
Malates / pharmacology*
Male
Mice
Mice, Inbred C57BL
Mice, Obese
Molecular Structure
Phenylbutyrates / administration & dosage
Phenylbutyrates / chemistry*
Phenylbutyrates / pharmacology*
Pyridines / administration & dosage
Pyridines / chemistry*
Pyridines / pharmacology*
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Symporters / antagonists & inhibitors*
Symporters / metabolism

Substances

Blood Glucose
Citrates
Malates
PF-06649298
PF-06761281
Phenylbutyrates
Pyridines
SLC13A5 protein, human
Symporters