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Optimization of a Dicarboxylic Series for in Vivo Inhibition of Citrate Transport by the Solute Carrier 13 (SLC13) Family.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2016 Feb 11; Vol. 59 (3), pp. 1165-75. Date of Electronic Publication: 2016 Jan 27. - Publication Year :
- 2016
-
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.
- Subjects :
- Animals
Biological Transport drug effects
Blood Glucose 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
Male
Mice
Mice, Inbred C57BL
Mice, Obese
Molecular Structure
Phenylbutyrates administration & dosage
Pyridines administration & dosage
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Symporters metabolism
Citrates metabolism
Malates chemistry
Malates pharmacology
Phenylbutyrates chemistry
Phenylbutyrates pharmacology
Pyridines chemistry
Pyridines pharmacology
Symporters antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 59
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 26734723
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.5b01752