Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Synthesis and SAR of Thiazolylmethylphenyl Glucoside as Novel C-Aryl Glucoside SGLT2 Inhibitors.

ABSTRACT: Novel C-aryl glucoside SGLT2 inhibitors containing the thiazole motif were designed and synthesized for biological evaluation. Among the compounds assayed, thiazole containing furanyl moiety 14v and thiophenyl moiety 14y demonstrated the best in vitro inhibitory activity against SGLT2 in this series to date (IC50 = 0.720 nM for 14v and IC50 = 0.772 nM for 14y). Both of these compounds have been further evaluated on a urinary glucose excretion test and the urine volumes excreted.

SUBMITTER: Song KS

PROVIDER: S-EPMC4018110 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Synthesis and SAR of Thiazolylmethylphenyl Glucoside as Novel C-Aryl Glucoside SGLT2 Inhibitors.

Song Kwang-Seop KS Lee Suk Ho SH Kim Min Ju MJ Seo Hee Jeong HJ Lee Junwon J Lee Sung-Han SH Jung Myung Eun ME Son Eun-Jung EJ Lee MinWoo M Kim Jeongmin J Lee Jinhwa J

ACS medicinal chemistry letters 20101213 2

Novel C-aryl glucoside SGLT2 inhibitors containing the thiazole motif were designed and synthesized for biological evaluation. Among the compounds assayed, thiazole containing furanyl moiety 14v and thiophenyl moiety 14y demonstrated the best in vitro inhibitory activity against SGLT2 in this series to date (IC50 = 0.720 nM for 14v and IC50 = 0.772 nM for 14y). Both of these compounds have been further evaluated on a urinary glucose excretion test and the urine volumes excreted. ...[more]

PMID: 24900297

Similar Datasets

Synthesis and SAR of Benzisothiazole- and Indolizine-β-d-glucopyranoside Inhibitors of SGLT2.

Project description:A series of benzisothiazole- and indolizine-β-d-glucopyranoside inhibitors of human SGLT2 are described. The synthesis of the C-linked heterocyclic glucosides took advantage of a palladium-catalyzed cross-coupling reaction between a glucal boronate and the corresponding bromo heterocycle. The compounds have been evaluated for their human SGLT2 inhibition potential using cell-based functional transporter assays, and their structure-activity relationships have been described. Benzisothiazole-C-glucoside 16d was found to be an inhibitor of SGLT2 with an IC50 of 10 nM.

| S-EPMC4007969 | biostudies-literature

Synthesis and Hybrid SAR Property Modeling of Novel Cholinesterase Inhibitors.

Project description:A library of novel 4-{[(benzyloxy)carbonyl]amino}-2-hydroxybenzoic acid amides was designed and synthesized in order to provide potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors; the in vitro inhibitory profile and selectivity index were specified. Benzyl (3-hydroxy-4-{[2-(trifluoromethoxy)phenyl]carbamoyl}phenyl)carbamate was the best AChE inhibitor with the inhibitory concentration of IC50 = 36.05 µM in the series, while benzyl {3-hydroxy-4-[(2-methoxyphenyl)carbamoyl]phenyl}-carbamate was the most potent BChE inhibitor (IC50 = 22.23 µM) with the highest selectivity for BChE (SI = 2.26). The cytotoxic effect was evaluated in vitro for promising AChE/BChE inhibitors. The newly synthesized adducts were subjected to the quantitative shape comparison with the generation of an averaged pharmacophore pattern. Noticeably, three pairs of fairly similar fluorine/bromine-containing compounds can potentially form the activity cliff that is manifested formally by high structure-activity landscape index (SALI) numerical values. The molecular docking study was conducted for the most potent AChE/BChE inhibitors, indicating that the hydrophobic interactions were overwhelmingly generated with Gln119, Asp70, Pro285, Thr120, and Trp82 aminoacid residues, while the hydrogen bond (HB)-donor ones were dominated with Thr120. π-stacking interactions were specified with the Trp82 aminoacid residue of chain A as well. Finally, the stability of chosen liganded enzymatic systems was assessed using the molecular dynamic simulations. An attempt was made to explain the noted differences of the selectivity index for the most potent molecules, especially those bearing unsubstituted and fluorinated methoxy group.

| S-EPMC8037530 | biostudies-literature

Concise and Stereodivergent Synthesis of Carbasugars Reveals Unexpected Structure-Activity Relationship (SAR) of SGLT2 Inhibition.

Project description:Carbasugar sodium-glucose cotransporter 2 (SGLT2) inhibitors are highly promising drug candidates for the treatment of Type 2 diabetes mellitus (T2DM). However, the clinical usage of carbasugar SGLT2 inhibitors has been underexplored, due to the lengthy synthetic routes and the lack of structure-activity relationship (SAR) studies of these compounds. Herein, we report a concise and stereodivergent synthetic route towards some novel carbasugar SGLT2 inhibitors, featuring an underexploited, regioselective, and stereospecific palladium-catalyzed allyl-aryl coupling reaction. This synthetic strategy, together with computational modeling, revealed the unexpected SAR of these carbasugar SGLT2 inhibitors, and enabled the discovery of a highly selective and potent SGLT2 inhibitor.

| S-EPMC5514135 | biostudies-literature

Synthesis and SAR studies of 1,4-benzoxazine MenB inhibitors: novel antibacterial agents against Mycobacterium tuberculosis.

Project description:Menaquinone is an essential component of the electron transport chain in many pathogens and consequently enzymes in the menaquinone biosynthesis pathway are potential drug targets for the development of novel antibacterial agents. In order to identify leads that target MenB, the 1,4-dihydroxy-2-naphthoyl-CoA synthase from Mycobacterium tuberculosis, a high-throughput screen was performed. Several 1,4-benzoxazines were identified in this screen and subsequent SAR studies resulted in the discovery of compounds with excellent antibacterial activity against M. tuberculosis H37Rv with MIC values as low as 0.6?g/ml. The 1,4-benzoxazine scaffold is thus a promising foundation for the development of antitubercular agents.

| S-EPMC2956582 | biostudies-literature

Synthesis and SAR of piperazine amides as novel c-jun N-terminal kinase (JNK) inhibitors.

Project description:A novel series of c-jun N-terminal kinase (JNK) inhibitors were designed and developed from a high-throughput-screening hit. Through the optimization of the piperazine amide 1, several potent compounds were discovered. The X-ray crystal structure of 4g showed a unique binding mode different from other well known JNK3 inhibitors.

| S-EPMC2737472 | biostudies-other

Rational Design, Synthesis, and SAR of a Novel Thiazolopyrimidinone Series of Selective PI3K-beta Inhibitors.

Project description:A novel thiazolopyrimidinone series of PI3K-beta selective inhibitors has been identified. This chemotype has provided an excellent tool compound, 18, that showed potent growth inhibition in the PTEN-deficient breast cancer cell line MDA-MB-468 under anchorage-independent conditions, and it also demonstrated pharmacodynamic effects and efficacy in a PTEN-deficient prostate cancer PC-3 xenograft mouse model.

| S-EPMC4025772 | biostudies-other

Synthesis, Structure, and SAR of Tetrahydropyran-Based LpxC Inhibitors.

Project description:In the search for novel Gram-negative agents, we performed a comprehensive search of the AstraZeneca collection and identified a tetrahydropyran-based matrix metalloprotease (MMP) inhibitor that demonstrated nanomolar inhibition of UDP-3-O-(acyl)-N-acetylglucosamine deacetylase (LpxC). Crystallographic studies in Aquifex aeolicus LpxC indicated the tetrahydropyran engaged in the same hydrogen bonds and van der Waals interactions as other known inhibitors. Systematic optimization of three locales on the scaffold provided compounds with improved Gram-negative activity. However, the optimization of LpxC activity was not accompanied by reduced inhibition of MMPs. Comparison of the crystal structure of the native product, UDP-3-O-(acyl)-glucosamine, in Aquifex aeolicus to the structure of a tetrahydropyran-based inhibitor indicates pathways for future optimization.

| S-EPMC4233352 | biostudies-literature

Structure-based virtual screening, synthesis and SAR of novel inhibitors of hepatitis C virus NS5B polymerase.

Project description:Hepatitis C virus (HCV) NS5B polymerase is a key target for the development of therapeutic agents aimed at the treatment of HCV infections. Here we report on the identification of novel allosteric inhibitors of HCV NS5B through a combination of structure-based virtual screening, synthesis and structure-activity relationship (SAR) optimization approach. Virtual screening of 260,000 compounds from the ChemBridge database against the tetracyclic indole inhibitor binding pocket of NS5B (allosteric pocket-1, AP-1), sequentially down-sized the library by 4 orders of magnitude to yield 23 candidates. In vitro evaluation of the NS5B inhibitory activity of the in-silico selected compounds resulted in 17% hit rate, identifying two novel chemotypes. Of these, compound 3, bearing the rhodanine scaffold, proved amenable for productive SAR exploration and synthetic modification. As a result, 25 derivatives that exhibited IC?? values ranging from 7.7 to 68.0 ?M were developed. Docking analysis of lead compound 28 within the tetracyclic indole- and benzylidene-binding allosteric pockets (AP-1 and AP-3, respectively) of NS5B revealed topological similarities between these two pockets. Compound 28, a novel rhodanine analog with NS5B inhibitory potency in the low micromolar level range may be a promising lead for future development of more potent NS5B inhibitors.

| S-EPMC2956004 | biostudies-literature

SGLT2 inhibitors and zebrafish

Project description:The CANVAS program revealed that the SGLT2 inhibitor canagliflozin increases the risk for lower-limb (minor) amputations in type 2 diabetics about a two-fold. On the contrary, the large RCTs with empagliflozin and dapagliflozin did not demonstrate a similar observation. Thus, a question arises whether the increased risk for minor amputations is associated only with canagliflozin or whether it is a class effect of SGLT2 inhibitors. Vascular disorders including defective angiogenesis are among the leading causes of lower-limb amputations. Therefore, here we examined the effects of empagliflozin, dapagliflozin, and canagliflozin on angiogenesis using zebrafish embryos and HUVECs.

2022-12-31 | GSE191046 | GEO

Synthesis and SAR of b-annulated 1,4-dihydropyridines define cardiomyogenic compounds as novel inhibitors of TGF? signaling.

Project description:A medium-throughput murine embryonic stem cell (mESC)-based high-content screening of 17000 small molecules for cardiogenesis led to the identification of a b-annulated 1,4-dihydropyridine (1,4-DHP) that inhibited transforming growth factor ? (TGF?)/Smad signaling by clearing the type II TGF? receptor from the cell surface. Because this is an unprecedented mechanism of action, we explored the series' structure-activity relationship (SAR) based on TGF? inhibition, and evaluated SAR aspects for cell-surface clearance of TGF? receptor II (TGFBR2) and for biological activity in mESCs. We determined a pharmacophore and generated 1,4-DHPs with IC(50)s for TGF? inhibition in the nanomolar range (e.g., compound 28, 170 nM). Stereochemical consequences of a chiral center at the 4-position was evaluated, revealing 10- to 15-fold more potent TGF? inhibition for the (+)- than the (-) enantiomer. This stereopreference was not observed for the low level inhibition against Activin A signaling and was reversed for effects on calcium handling in HL-1 cells.

| S-EPMC3518459 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data