Browse
Submit Data
Databases
API
Help

Dataset Information

20 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Synthesis and biological evaluation of cyclic sulfamide derivatives as 11?-hydroxysteroid dehydrogenase 1 inhibitors.

ABSTRACT: A new series of cyclic sulfamide derivatives were synthesized and evaluated for their ability to inhibit 11?-HSD1. Among this series, 18e showed good in vitro activity toward human 11?-HSD1, selectivity against 11?-HSD2, microsomal stability, and pharmacokinetic and safety profiles (hERG, CYP, and acute toxicity). Additionally, 18e exhibited good in vivo efficacy in rat and monkey models.

SUBMITTER: Kim SH

PROVIDER: S-EPMC4025780 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Synthesis and biological evaluation of cyclic sulfamide derivatives as 11β-hydroxysteroid dehydrogenase 1 inhibitors.

Kim Se Hoan SH Bok Ju Han JH Lee Jae Hong JH Kim Il Hyang IH Kwon Sung Wook SW Lee Gui Bin GB Kang Seung Kyu SK Park Ji Seon JS Jung Won Hoon WH Kim Hee Yeon HY Rhee Sang Dal SD Ahn Sung Hoon SH Bae Myung Ae MA Ha Deok Chan DC Kim Ki Young KY Ahn Jin Hee JH

ACS medicinal chemistry letters 20120117 2

A new series of cyclic sulfamide derivatives were synthesized and evaluated for their ability to inhibit 11β-HSD1. Among this series, 18e showed good in vitro activity toward human 11β-HSD1, selectivity against 11β-HSD2, microsomal stability, and pharmacokinetic and safety profiles (hERG, CYP, and acute toxicity). Additionally, 18e exhibited good in vivo efficacy in rat and monkey models. ...[more]

PMID: 24900439

Similar Datasets

Adamantyl ethanone pyridyl derivatives: potent and selective inhibitors of human 11?-hydroxysteroid dehydrogenase type?1.

Project description:Elevated levels of active glucocorticoids have been implicated in the development of several phenotypes of metabolic syndrome, such as type?2 diabetes and obesity. 11?-Hydroxysteroid dehydrogenase type?1 (11?-HSD1) catalyses the intracellular conversion of inactive cortisone to cortisol. Selective 11?-HSD1 inhibitors have shown beneficial effects in various conditions, including diabetes, dyslipidemia and obesity. A series of adamantyl ethanone pyridyl derivatives has been identified, providing potent and selective inhibitors of human 11?-HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11?-HSD1 and are selective for this isoform, with no activity against 11?-HSD2 and 17?-HSD1. Structure-activity relationship studies reveal that an unsubstituted pyridine tethered to an adamantyl ethanone motif through an ether or sulfoxide linker provides a suitable pharmacophore for activity. The most potent inhibitors have IC?? values around 34-48?nM against human 11?-HSD1, display reasonable metabolic stability in human liver microsomes, and weak inhibition of key human CYP450 enzymes.

| S-EPMC3179844 | biostudies-literature

Design, synthesis and biological evaluation of sulfamide and triazole benzodiazepines as novel p53-MDM2 inhibitors.

Project description:A series of sulfamide and triazole benzodiazepines were obtained with the principle of bioisosterism. The p53-murine double minute 2 (MDM2) inhibitory activity and in vitro antitumor activity were evaluated. Most of the novel benzodiazepines exhibited moderate protein binding inhibitory activity. Particularly, triazole benzodiazepines showed good inhibitory activity and antitumor potency. Compound 16 had promising antitumor activity against the U-2 OS human osteosarcoma cell line with an IC50 value of 4.17 ?M, which was much better than that of nutlin-3. The molecular docking model also successfully predicted that this class of compounds mimicked the three critical residues of p53 binding to MDM2.

| S-EPMC4200789 | biostudies-literature

Synthesis and biological evaluation of nicotinamide derivatives with a diarylamine-modified scaffold as succinate dehydrogenase inhibitors.

Project description:Six novel nicotinamide derivatives bearing a diarylamine-modified scaffold with flexible heterocyclic patterns were designed, synthesized, and characterized in detail via Hydrogen nuclear magnetic resonance (1H-NMR), Carbon nuclear magnetic resonance (13C-NMR), and Electrospray ionization mass spectrometry (ESI-MS). Their fungicidal activities and succinate dehydrogenase (SDH) enzymatic inhibitory abilities were evaluated. Preliminary fungicidal bioassay results showed that some of the target compounds exhibited moderate fungicidal activity. Among them, compound 4a showed 40.54% inhibition against Botrytis cinerea fungi. An SDH enzymatic inhibition assay revealed that the IC50 of compound 4b was 3.18 µM. This result indicated that the enzymatic inhibition level of 4b was similar to that of boscalid. Compound 4f exhibited superior comprehensive fungicidal and SDH enzymatic inhibitory activities. Molecular docking results suggested that 4f could bind well to the substrate cavity and the entrance cavity of SDH (1YQ3). In particular, 4f could react with the key catalytic site Arg 297. This phenomenon implied that 4f could act as the lead compound for further optimization.

| S-EPMC7024744 | biostudies-literature

Derivatives of (phenylsulfonamido-methyl)nicotine and (phenylsulfonamido-methyl)thiazole as novel 11beta-hydroxysteroid dehydrogenase type 1 inhibitors: synthesis and biological activities in vitro.

Project description:AimTo design and synthese a novel class of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitors, featuring the (phenylsulfonamido-methyl)pyridine and (phenylsulfonamido-methyl)thiazole framework.MethodsOur initial lead 4-(phenylsulfonamido-methyl)benzamides were modified. Inhibition of human and mouse 11beta-HSD1 enzymatic activities by the new compounds was determined by a scintillation proximity assay (SPA) using microsomes containing 11beta-HSD1.ResultsSixteen new compounds (6a-6h, 7a-7h) were designed, synthesized and bioassayed. In dose-response studies, several compounds showed strong inhibitory activities with IC50 values at nanomolar or low nanomolar concentrations. Structure-activity relationships are also discussed with respect to molecular docking results.ConclusionThis study provides two promising new templates for 11beta-HSD1 inhibitors.

| S-EPMC4007184 | biostudies-literature

Synthesis and biological evaluation of thiophene derivatives as acetylcholinesterase inhibitors.

Project description:A series of new thiophene derivatives has been synthesized using the Gewald protocol. The acetylcholinesterase inhibition activity was assayed according to Ellman's method using donepezil as reference. Some of the compounds were found to be more potent inhibitors than the reference. 2-(2-(4-(4-Methoxyphenyl)piperazin-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (IIId) showed 60% inhibition, compared to only 40% inhibition by donepezil.

| S-EPMC6268334 | biostudies-literature

Optimization of 1,2,4-Triazolopyridines as Inhibitors of Human 11?-Hydroxysteroid Dehydrogenase Type 1 (11?-HSD-1).

Project description:Small alkyl groups and spirocyclic-aromatic rings directly attached to the left side and right side of the 1,2,4-triazolopyridines (TZP), respectively, were found to be potent and selective inhibitors of human 11?-hydroxysteroid dehydrogenase-type 1 (11?-HSD-1) enzyme. 3-(1-(4-Chlorophenyl)cyclopropyl)-8-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridine (9f) was identified as a potent inhibitor of the 11?-HSD-1 enzyme with reduced Pregnane-X receptor (PXR) transactivation activity. The binding orientation of this TZP series was revealed by X-ray crystallography structure studies.

| S-EPMC4094253 | biostudies-literature

Discovery of adamantyl heterocyclic ketones as potent 11?-hydroxysteroid dehydrogenase type?1 inhibitors.

Project description:11?-hydroxysteroid dehydrogenase type?1 (11?-HSD1) plays a key role in converting intracellular cortisone to physiologically active cortisol, which is implicated in the development of several phenotypes of metabolic syndrome. Inhibition of 11?-HSD1 activity with selective inhibitors has beneficial effects on various conditions, including diabetes, dyslipidemia and obesity, and therefore constitutes a promising strategy to discover novel therapies for metabolic and cardiovascular diseases. A series of novel adamantyl heterocyclic ketones provides potent and selective inhibitors of human 11?-HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11?-HSD1 and are selective with no activity against 11?-HSD2 and 17?-HSD1. Selected potent 11?-HSD1 inhibitors show moderate metabolic stability upon incubation with human liver microsomes and weak inhibition of human CYP450 enzymes.

| S-EPMC3170876 | biostudies-literature

Adamantyl carboxamides and acetamides as potent human 11?-hydroxysteroid dehydrogenase type 1 inhibitors.

Project description:The modulation of 11?-HSD1 activity with selective inhibitors has beneficial effects on various metabolic disorders including insulin resistance, dyslipidemia and obesity. Here we report the discovery of a series of novel adamantyl carboxamide and acetamide derivatives as selective inhibitors of human 11?-HSD1 in HEK-293 cells transfected with the HSD11B1 gene. Optimization based on an initially identified 11?-HSD1 inhibitor (3) led to the discovery of potent inhibitors with IC(50) values in the 100 nM range. These compounds are also highly selective 11?-HSD1 inhibitors with no activity against 11?-HSD2 and 17?-HSD1. Compound 15 (IC(50)=114 nM) with weak inhibitory activity against the key human cytochrome P450 enzymes and moderate stability in incubation with human liver microsomes is worthy of further development. Importantly, compound 41 (IC(50)=280 nM) provides a new lead that incorporates an adamantyl group surrogate and should enable further series diversification.

| S-EPMC3510433 | biostudies-literature

Discovery of 2-Alkyl-1-arylsulfonylprolinamides as 11?-Hydroxysteroid Dehydrogenase Type 1 Inhibitors.

Project description:On the basis of scaffold hopping, a novel series of 2-alkyl-1-arylsulfonylprolinamides was discovered as 11?-hydroxysteroid dehydrogenase type 1 (11?-HSD-1) inhibitors. A representative compound 4ek, obtained through SAR and structure optimization studies, demonstrates excellent in vitro potency against 11?-HSD-1 and dose-dependent in vivo inhibition of 11?-HSD-1 in a prednisone/prednisolone transformation biomarker study in mice.

| S-EPMC4025654 | biostudies-literature

Indole Derivatives as Cyclooxygenase Inhibitors: Synthesis, Biological Evaluation and Docking Studies.

Project description:A new series of 2-(5-methoxy-2-methyl-1H-indol-3-yl)-N?-[(E)-(substituted phenyl) methylidene] acetohydrazide derivatives (S1?S18) were synthesized and evaluated for their anti-inflammatory activity, analgesic activity, ulcerogenic activity, lipid peroxidation, ulcer index and cyclooxygenase expression activities. All the synthesized compounds were in good agreement with spectral and elemental analysis. Three synthesized compounds (S3, S7 and S14) have shown significant anti-inflammatory activity as compared to the reference drug indomethacin. Compound S3 was further tested for ulcerogenic index and cyclooxygenase (COX) expression activity. It was selectively inhibiting COX-2 expression and providing the gastric sparing activity. Docking studies have revealed the potential of these compounds to bind with COX-2 enzyme. Compound S3 formed a hydrogen bond between OH of Tyr 355 and NH? of Arg 120 with carbonyl group and this hydrogen bond was similar to that formed by indomethacin. This study provides insight for compound S3, as a new lead compound as anti-inflammatory agent and selective COX-2 inhibitor.

| S-EPMC6100013 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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