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Relevant academic research and scientific papers

Synthesis and biological evaluation of novel potent FFA1 agonists containing 2,3-dihydrobenzo[b][1,4]dioxine

FFA1 (free fatty acid receptor 1) has emerged as an attractive antidiabetic target due to its role in mediating the enhancement of glucose-stimulated insulin secretion in pancreatic β cells with a low risk of hypoglycemia. Many reported FFA1 agonists possessed somewhat pharmacokinetic and/or safety issues. Herein, we describe the identification of 2,3-dihydrobenzo[b][1,4]dioxine as a novel scaffold for FFA1 agonists. Comprehensive structure-activity relationship study based on this scaffold led to the discovery of (S)-3-(4-(((S)-7-(4-methoxyphenyl)-2,3-dihydrobenzo [b][1,4]dioxin-2-yl)methoxy) phenyl)hex-4-ynoic acid (26k), which displayed a potent FFA1 agonistic activity and good pharmacokinetic profiles. Subsequent in vivo studies demonstrated that compound 26k significantly improved the glucose tolerance in ICR mice. In summary, compound 26k is a promising drug candidate for further investigation.

Aromatic propionic acid derivative, preparation method and uses thereof

The present invention discloses a compound represented by a general formula I or a tautomer, a racemate, an enantiomer, a diastereomer, a mixture and a pharmaceutically acceptable salt thereof, wherein each substituent is defined in the specification and claims. According to the present invention, the compound has obvious agonistic activity and selectivity to a GPR40 receptor in vitro, and the oral administration of the compound can significantly reduce the blood glucose concentration of rats after oral administration of glucose and increase the glucose tolerance capacity of rats in a dose-dependent manner so as to provide the good in vivo glucose lowering effect and achieve excellent pharmacokinetic properties and excellent drug-forming properties, such that the compound of the present invention can be used for the preparation of drugs for treating metabolic diseases such as diabetes and the like.

Design and optimization of 2,3-dihydrobenzo[b][1,4]dioxine propanoic acids as novel GPR40 agonists with improved pharmacokinetic and safety profiles

GPR40 has become a new potential therapeutic target for the treatment of diabetes due to its role in mediating the enhancement of glucose-stimulated insulin secretion in pancreatic β cells with a low risk of hypoglycemia. As an effort to extend the chemical space and identify structurally distinct GPR40 agonists with improved liver safety, a novel series of fused-ring phenyl propanoic acid analogues were designed. Comprehensive structure-activity relationship studies around novel scaffolds were conducted and led to several analogues exhibited potent GPR40 agonistic activities and high selectivity against other fatty acid receptors. Further evaluation of pharmacokinetic (PK) profiles and in vivo efficacy identified compound 40a with excellent PK properties and significant glucose-lowering efficacy during an oral glucose tolerance test. In addition, compound 40a displayed lower hepatobiliary transporter inhibition and favorable druggability. All results indicate that compound 40a is a promising candidate for further development.

MODULATORS OF DOPAMINE NEUROTRANSMISSION

The present invention relates to novel 1-(2,3-dihydro-1,4-benzodioxin-2-yl)- methanamine derivatives, useful as modulators of dopamine neurotransmission, and more specifically as dopaminergic stabilizers. In other aspects the invention relates to the use of these compounds in a method for therapy and to pharmaceutical compositions comprising the compounds of the invention.