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5-Alkyl-2-urea-Substituted Pyridines: Identification of Efficacious Glucokinase Activators with Improved Properties.

ABSTRACT: Two 1-(4-aryl-5-alkyl-pyridin-2-yl)-3-methylurea glucokinase activators were identified with robust in vivo efficacy. These two compounds possessed higher solubilities than the previously identified triaryl compounds (i.e., AM-2394). Structure-activity relationship studies are presented along with relevant pharmacokinetic and in vivo data.

SUBMITTER: Kohn TJ

PROVIDER: S-EPMC4948010 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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5-Alkyl-2-urea-Substituted Pyridines: Identification of Efficacious Glucokinase Activators with Improved Properties.

Kohn Todd J TJ Du Xiaohui X Lai SuJen S Xiong YuMei Y Komorowski Renee R Veniant Murielle M Fu Zice Z Jiao Xianyun X Pattaropong Vatee V Chow David D Cardozo Mario M Jin Lixia L Conn Marion M DeWolf Walter E WE Kraser Christopher F CF Hinklin Ronald J RJ Boys Mark L ML Medina Julio C JC Houze Jonathan J Dransfield Paul P Coward Peter P

ACS medicinal chemistry letters 20160601 7

Two 1-(4-aryl-5-alkyl-pyridin-2-yl)-3-methylurea glucokinase activators were identified with robust in vivo efficacy. These two compounds possessed higher solubilities than the previously identified triaryl compounds (i.e., AM-2394). Structure-activity relationship studies are presented along with relevant pharmacokinetic and in vivo data. ...[more]

PMID: 27437074

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C5-Alkyl-2-methylurea-Substituted Pyridines as a New Class of Glucokinase Activators.

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Synthesis of multi-substituted pyridines from ylidenemalononitriles and their emission properties.

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Structure-Dependent Developmental Toxicity of Alkyl-Substituted Naphthalenes

Project description:Naphthalene and its alkyl-substituted derivatives are among the most abundant polycyclic aromatic hydrocarbons (PAHs) in environmental and human exposure studies, yet their developmental toxicity and mode of action remain poorly understood due to challenges in testing of semi-volatile compounds. This study developed a vial based high through-put method to effectively assess the activity of naphthalenes and a set of 24 alkyl-substituted naphthalenes. Early life stage zebrafish were exposed to a concentration series of each chemical (0-50 µM) in rotating sealed glass vials to minimize volatilization. Benchmark concentration (BMC50) values were calculated for morphological endpoints and lowest effect levels were determined for behavioral effects. The data were assessed for evidence of a narcotic mode of action using body burden measurements for select chemicals and logKow modeling. Targeted transcriptomics at a single concentration and timepoint as well as in silico molecular docking were conducted to generate mode of action hypothesis. The vial method enabled detection of highly variable developmental toxicity not previously observed using standard 96-well plate exposures. LogKow and body burden were poor predictors of toxicity, suggesting a non-narcotic mode of action. Transcriptomic analysis revealed a limited but notable set of differentially expressed genes, with evidence for the disruption of glucocorticoid signaling pathways. Molecular docking identified potential protein targets (e.g., CYP1A2, NT5E, FOLR1) that may mediate observed effects. This study demonstrates the importance of appropriate exposure methods for semi-volatile compounds, reveals structure-dependent toxicity among alkyl-substituted naphthalenes, and provides a foundation for further mechanistic studies and improved risk assessment of alkyl-substituted PAHs.

2025-05-23 | GSE296410 | GEO

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Project description:A simple, modular method to prepare highly substituted pyridines is disclosed. The method employs a cascade reaction comprising (1) a novel N-iminative, Cu-catalyzed cross-coupling of alkenylboronic acids at the N-O bond of alpha,beta-unsaturated ketoxime O-pentafluorobenzoates, (2) electrocyclization of the resulting 3-azatriene, and (3) air oxidation affording highly substituted pyridines in moderate to excellent isolated yields (43-91%). Starting materials are readily available, and functional group tolerance is very good.

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Project description:Dearomatization is an effective method to transform readily available N-heterocycles into partially saturated motifs. Manipulation of dihydro-derivatives holds great potential and provides access to a variety of semi-saturated N-heterocyclic building blocks. However, current strategies are limited in scope and the use of sensitive reagents restricts the applicability in synthetic laboratories. Herein, we report the synthesis of a broad variety of N-substituted 1,4- and 1,2-dihydropyridines by very mild and selective reduction with amine borane for the first time.

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Comparative docking assessment of glucokinase interactions with its allosteric activators.

Project description:Glucokinase (GK) is expressed in multiple organs and plays a key role in hepatic glucose metabolism and pancreatic insulin secretion. GK could indeed serve as pacemaker of glycolysis and could be an attractive target for type 2 diabetes (T2D). The recent preclinical data of first GK activator RO-28-1675 has opened up a new field of GK activation as a powerful tool in T2D therapies. The GK allosteric site is located ~20A away from glucose binding site. Chemical structure of Glucokinase activators (GKA) includes three chemical arms; all consisting of cyclic moiety and joined in a shape resembling the letter Y. In this study, comparative docking assessment using Autodock4 revealed that the three arms bind to three aromatic/hydrophobic subpockets at the allosteric site. Our dockings have overall consistency with experimental data in both docking modes and simulated binding free energies, and offer insights on understanding GK/GKA interactions and further GKA design. Specifically, for the first pocket, involvement of Arg63 as key residue in two specific hydrogen-bond formations with all allosteric activators defines the binding feature; for the second pocket, it has the most diverse binding interactions, mostly aromatic, hydrophobic and multiple hydrogen bonds. The site has the best potential for further GKA optimization by utilizing aromatic heterocycles and hydrogen bond forming linkers to build the GKA 2(nd) arm.

| S-EPMC2803441 | biostudies-literature

Structure-Dependent Developmental Toxicity of Alkyl-Substituted Naphthalenes

Project description:Structure-Dependent Developmental Toxicity of Alkyl-Substituted Naphthalenes

| PRJNA1259243 | ENA

Exploratory toxicology studies of 2,3-substituted imidazo[1,2-<i>a</i>]pyridines with antiparasitic and anti-inflammatory properties.

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| S-EPMC9618103 | biostudies-literature

New-Generation Glucokinase Activators: Potential Game-Changers in Type 2 Diabetes Treatment.

Project description:Achieving glycemic control and sustaining functional pancreatic β-cell activity remains an unmet medical need in the treatment of type 2 diabetes mellitus (T2DM). Glucokinase activators (GKAs) constitute a class of anti-diabetic drugs designed to regulate blood sugar levels and enhance β-cell function in patients with diabetes. A significant progression in GKA development is underway to address the limitations of earlier generations. Dorzagliatin, a dual-acting GKA, targets both the liver and pancreas and has successfully completed two phase III trials, demonstrating favorable results in diabetes treatment. The hepato-selective GKA, TTP399, emerges as a strong contender, displaying clinically noteworthy outcomes with minimal adverse effects. This paper seeks to review the current literature, delve into the mechanisms of action of these new-generation GKAs, and assess their efficacy and safety in treating T2DM based on published preclinical studies and recent clinical trials.

| S-EPMC10779250 | biostudies-literature

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