Design, synthesis and evaluation of novel zwitterionic compounds as PPARalpha/gamma dual agonists (1).

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Shibata Y, Kagechika K, Yamaguchi M, Kubo H, Usui H

Design, synthesis and evaluation of novel zwitterionic compounds as PPARalpha/gamma dual agonists (1).

Bioorg Med Chem Lett. 2012 Dec 1;22(23):7075-9. doi: 10.1016/j.bmcl.2012.09.092. Epub 2012 Oct 2.

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23084275 [ View in PubMed

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Abstract

We describe here the design, syntheses and structure-activity relationships (SAR) of novel zwitterionic compounds as non-thiazolidinedion (TZD) based peroxisome proliferator activated receptor (PPAR) alpha/gamma dual agonists. We commenced the medicinal research with compound 1 originated by Eli Lilly, which was reported to possess PPAR alpha/gamma dual agonist activity. We incorporated an amine linker and optimized it on the nitrogen of the linker, thereby envisioning the enhancement of the PPAR alpha/gamma dual agonist activity together with altering the physicochemical properties. As a result, we could generate compounds showing the PPAR alpha/gamma dual activity, especially among which compound 22e had a franylmethyl group on the linker and 2,6-dimethyl phenyl ring at the carboxylic acid head group furnishing a highly potent dual agonist activity, together with a great glucose lowering effect. Moreover, it remedied the lipid profile, that is, triglyceride without body weight gain in the db/db mice model.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
(2S)-2-ETHOXY-3-{4-[2-(10H-PHENOXAZIN-10-YL)ETHOXY]PHENYL}PROPANOIC ACID	Peroxisome proliferator-activated receptor gamma	EC 50 (nM)	600	N/A	N/A	Details
Tesaglitazar	Peroxisome proliferator-activated receptor alpha	EC 50 (nM)	1200	N/A	N/A	Details
Tesaglitazar	Peroxisome proliferator-activated receptor gamma	EC 50 (nM)	1300	N/A	N/A	Details