Dataset Information

Structure-Activity Relationship of Novel and Selective Biaryl-Chroman GPR40 AgoPAMs.

ABSTRACT: A series of biaryl chromans exhibiting potent and selective agonism for the GPR40 receptor with positive allosteric modulation of endogenous ligands (AgoPAM) were discovered as potential therapeutics for the treatment of type II diabetes. Optimization of physicochemical properties through modification of the pendant aryl rings resulted in the identification of compound AP5, which possesses an improved metabolic profile while demonstrating sustained glucose lowering.

SUBMITTER: Chen HY

PROVIDER: S-EPMC6047031 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Structure-Activity Relationship of Novel and Selective Biaryl-Chroman GPR40 AgoPAMs.

Chen Helen Y HY Plummer Christopher W CW Xiao Dong D Chobanian Harry R HR DeMong Duane D Miller Michael M Trujillo Maria E ME Kirkland Melissa M Kosinski Daniel D Mane Joel J Pachanski Michele M Cheewatrakoolpong Boonlert B Di Salvo Jerry J Thomas-Fowlkes Brande B Souza Sarah S Tatosian Daniel A DA Chen Qing Q Hafey Michael J MJ Houle Robert R Nolting Andrew F AF Orr Robert R Ehrhart Juliann J Weinglass Adam B AB Tschirret-Guth Richard R Howard Andrew D AD Colletti Steven L SL

ACS medicinal chemistry letters 20180614 7

A series of biaryl chromans exhibiting potent and selective agonism for the GPR40 receptor with positive allosteric modulation of endogenous ligands (AgoPAM) were discovered as potential therapeutics for the treatment of type II diabetes. Optimization of physicochemical properties through modification of the pendant aryl rings resulted in the identification of compound <i>AP5</i>, which possesses an improved metabolic profile while demonstrating sustained glucose lowering. ...[more]

PMID: 30034601

Similar Datasets

Project description:Human norovirus is the leading cause of acute gastroenteritis worldwide, affecting every year 685 million people. Norovirus outbreaks are associated with very significant economic losses, with an estimated societal cost of 60 billion USD per year. Despite this, no therapeutic options or vaccines are currently available to treat or prevent this infection. An antiviral therapy that can be used as treatment and as a prophylactic measure in the case of outbreaks is urgently needed. We previously described the computer-aided design and synthesis of novel small-molecule agents able to inhibit the replication of human norovirus in cell-based systems. These compounds are non-nucleoside inhibitors of the viral polymerase and are characterized by a terminal para-substituted phenyl group connected to a central phenyl ring by an amide-thioamide linker, and a terminal thiophene ring. Here we describe new modifications of these scaffolds focused on exploring the role of the substituent at the para position of the terminal phenyl ring and on removing the thioamide portion of the amide-thioamide linker, to further explore structure-activity relationships (SARs) and improve antiviral properties. According to three to four-step synthetic routes, we prepared thirty novel compounds, which were then evaluated against the replication of both murine (MNV) and human (HuNoV) norovirus in cells. Derivatives in which the terminal phenyl group has been replaced by an unsubstituted benzoxazole or indole, and the thioamide component of the amide-thioamide linker has been removed, showed promising results in inhibiting HuNoV replication at low micromolar concentrations. Particularly, compound 28 was found to have an EC50 against HuNoV of 0.9 µM. Although the most active novel derivatives were also associated with an increased cytotoxicity in the human cell line, these compounds represent a very promising starting point for the development of new analogues with reduced cytotoxicity and improved selectivity indexes. In addition, the experimental biological data have been used to create an initial 3D quantitative structure-activity relationship model, which could be used to guide the future design of novel potential anti-norovirus agents.

Dataset Information

Structure-Activity Relationship of Novel and Selective Biaryl-Chroman GPR40 AgoPAMs.

Publications

Structure-Activity Relationship of Novel and Selective Biaryl-Chroman GPR40 AgoPAMs.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure