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

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 viv...

Full description

Saved in:

Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 59; no. 3; pp. 1165 - 1175
Main Authors:	Huard, Kim, Gosset, James R, Montgomery, Justin I, Gilbert, Adam, Hayward, Matthew M, Magee, Thomas V, Cabral, Shawn, Uccello, Daniel P, Bahnck, Kevin, Brown, Janice, Purkal, Julie, Gorgoglione, Matthew, Lanba, Adhiraj, Futatsugi, Kentaro, Herr, Michael, Genung, Nathan E, Aspnes, Gary, Polivkova, Jana, Garcia-Irizarry, Carmen N, Li, Qifang, Canterbury, Daniel, Niosi, Mark, Vera, Nicholas B, Li, Zhenhong, Khunte, Bhagyashree, Siderewicz, Jaclyn, Rolph, Timothy, Erion, Derek M
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 11-02-2016
Subjects:	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
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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 [14C]citrate uptake in liver and kidney in vivo, resulting in modest reductions in plasma glucose concentrations.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/acs.jmedchem.5b01752