Browse
Submit Data
Databases
API
Help

Dataset Information

9 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Discovery and Preliminary SAR of Arylpiperazines as Novel, Brainpenetrant Antiprion Compounds.

ABSTRACT: Prion diseases are a group of fatal neurodegenerative disorders that include Creutzfeldt-Jakob disease (CJD) and kuru in humans, BSE in cattle, and scrapie in sheep. Such illnesses are caused by the conversion and accumulation of a misfolded pathogenic isoform (termed PrP^Sc) of a normally benign, host cellular protein, denoted PrP^C. We employed high-throughput screening (HTS) ELISAs to evaluate compounds for their ability to reduce the level of PrP^Sc in Rocky Mountain Laboratory (RML) prion-infected mouse neuroblastoma cells (ScN2a-cl3). Arylpiperazines were among the active compounds identified but the initial hits suffered from low potency and poor drug-likeness. The best of those hits, such as 1, 7, 13, and 19, displayed moderate antiprion activity with EC₅₀ values in the micromolar range. Key analogs were designed and synthesized based on the SAR, with analogs 41, 44, 46, and 47 found to have sub-micromolar potency. Analogs 41 and 44 were able to penetrate the blood-brain barrier (BBB) and achieved excellent drug concentrations in the brains of mice after oral dosing. These compounds represent good starting points for further lead optimization in our pursuit of potential drug candidates for the treatment of prion diseases.

SUBMITTER: Li Z

PROVIDER: S-EPMC3704178 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Discovery of 2-aminothiazoles as potent antiprion compounds.

Project description:Prion diseases are fatal, untreatable neurodegenerative diseases caused by the accumulation of the misfolded, infectious isoform of the prion protein (PrP), termed PrP(Sc). In an effort to identify novel inhibitors of prion formation, we utilized a high-throughput enzyme-linked immunosorbent assay (ELISA) to evaluate PrP(Sc) reduction in prion-infected neuroblastoma cell lines (ScN2a). We screened a library of approximately 10,000 diverse small molecules in 96-well format and identified 121 compounds that reduced PrP(Sc) levels at a concentration of 5 microM. Four chemical scaffolds were identified as potential candidates for chemical optimization based on the presence of preliminary structure-activity relationships (SAR) derived from the primary screening data. A follow-up analysis of a group of commercially available 2-aminothiazoles showed this class as generally active in ScN2a cells. Our results establish 2-aminothiazoles as promising candidates for efficacy studies of animals and validate our drug discovery platform as a viable strategy for the identification of novel lead compounds with antiprion properties.

| S-EPMC2838138 | biostudies-literature

Mechanistic insights into the cure of prion disease by novel antiprion compounds.

Project description:Prion diseases are fatal neurodegenerative disorders. Identification of possible therapeutic tools is important in the search for a potential treatment for these diseases. Congo red is an azo dye that has been used for many years to detect abnormal prion protein in the brains of diseased patients or animals. Congo red has little therapeutic potential for the treatment of these diseases due to toxicity and poor permeation of the blood-brain barrier. We have prepared two Congo red derivatives, designed without these liabilities, with potent activity in cellular models of prion disease. One of these compounds cured cells of the transmissible agent. The mechanism of action of these compounds is possibly multifactorial. The high affinity of Congo red derivatives, including compounds that are ineffective and are effective at the cure of prion disease, for abnormally folded prion protein suggests that the amyloidophylic property of these derivatives is not as critical to the mechanism of action as other effects. Congo red derivatives that are effective at the cure of prion disease increased the degradation of abnormal PrP by the proteasome. Therefore, the principal mechanism of action of the Congo red analogues was to prevent inhibition of proteasomal activity by PrPSc.

| S-EPMC2045489 | biostudies-literature

Optimization of Arylamides as Novel, Potent and Brain-penetrant Antiprion Lead Compounds.

Project description:The prion diseases caused by PrPSc, an alternatively folded form of the cellular prion protein (PrPC), are rapidly progressive, fatal, and untreatable neurodegenerative syndromes. We employed HTS ELISA assays to identify compounds that lower the level of PrPSc in prion-infected mouse neuroblastoma (ScN2a-cl3) cells and identified a series of arylamides. SAR studies indicated that small amides with one aromatic, or heteroaromatic ring, on each side of the amide bond are of modest potency. Of note, benzamide (7), with an EC50 of 2200 nM, was one of only a few arylamide hits with a piperazine group on its aniline moiety. The basic piperazine nitrogen can be protonated at physiologic pH, improving solubility, and therefore we wanted to exploit this feature in our search for a drug candidate. An SAR campaign resulted in several key analogs, including a set with biaryl groups introduced on the carbonyl side for improved potency. Several of these biaryl analogs have submicromolar potency, with the most potent analog 17 having an EC50 = 22 nM. More importantly, 17 and several biarylamides (20, 24, 26, 27) were able to traverse the BBB and displayed excellent drug levels in the brains of mice following oral dosing. These biarylamides may represent good starting points for further lead optimization for the identification of potential drug candidates for the treatment of prion diseases.

| S-EPMC3746989 | biostudies-literature

Discovery and preliminary SAR of bisbenzylisoquinoline alkaloids as inducers of C/EBP?.

Project description:A high throughput in vitro screen has been developed to identify substances that induce expression of C/EBP? in tumor cells. An extract of the fruit of Gyrocarpus jacquinii showed induction of C/EBP? activity that was attributed to the bisbenzylisoquinoline (BBIQ) alkaloid pheanthine (13) by dereplication analysis. The research project was broadened to assess the effect of other natural BBIQ structural types occurring outside the genus Gyrocarpus. Several of the 28 compounds assayed showed enhancement of C/EBP? induction in U937 cells. The results of this study should encourage future efforts toward obtaining and screening a larger set of both natural and synthetic analogs of this interesting group of alkaloids.

| S-EPMC3430122 | biostudies-literature

Discovery and SAR study of piperidine-based derivatives as novel influenza virus inhibitors.

Project description:A series of piperidine-based derivatives were identified as novel and potent inhibitors of the influenza virus through structural modification of a compound that was selected from a high-throughput screen. Various analogues were synthesized and confirmed as inhibitors. The structure–activity relationship (SAR) studies suggested that the ether linkage between the quinoline and piperidine is critical for the inhibitory activity. The optimized compound tert-butyl 4-(quinolin-4-yloxy)piperidine-1-carboxylate 11e had an excellent inhibitory activity against influenza virus infection from a variety of influenza virus strains, with EC50 values as low as 0.05 ?M. The selectivity index value (SI = MLD50/EC50) of 11e is over 160000 based on cytotoxicity, measured by MTT assays of three cell lines. We carried out a time-of-addition experiment to delineate the mechanism of inhibition. The result indicates that 11e interferes with the early to middle stage of influenza virus replication.

| S-EPMC4177008 | biostudies-literature

Variety of antiprion compounds discovered through an in silico screen based on cellular-form prion protein structure: Correlation between antiprion activity and binding affinity.

Project description:Transmissible spongiform encephalopathies are associated with the conformational conversion of the prion protein from the cellular form (PrP(C)) to the scrapie form. This process could be disrupted by stabilizing the PrP(C) conformation, using a specific ligand identified as a chemical chaperone. To discover such compounds, we employed an in silico screen that was based on the nuclear magnetic resonance structure of PrP(C). In combination, we performed ex vivo screening using the Fukuoka-1 strain-infected neuronal mouse cell line at a compound concentration of 10 microM and surface plasmon resonance. Initially, we selected 590 compounds according to the calculated docked energy and finally discovered 24 efficient antiprion compounds, whose chemical structures are quite diverse. Surface plasmon resonance studies showed that the binding affinities of compounds for PrP(C) roughly correlated with the compounds' antiprion activities, indicating that the identification of chemical chaperones that bind to the PrP(C) structure and stabilize it is one efficient strategy for antiprion drug discovery. However, some compounds possessed antiprion activities with low affinities for PrP(C), indicating a mechanism involving additional modulation factors. We classified the compounds roughly into five categories: (i) binding and effective, (ii) low binding and effective, (iii) binding and not effective, (iv) low binding and not effective, and (v) acceleration. In conclusion, we found a spectrum of compounds, many of which are able to modulate the pathogenic conversion reaction. The appropriate categorization of these diverse compounds would facilitate antiprion drug discovery and help to elucidate the pathogenic conversion mechanism.

| S-EPMC2630596 | biostudies-literature

African trypanosomiasis: Synthesis & SAR enabling novel drug discovery of ubiquinol mimics for trypanosome alternative oxidase.

Project description:African trypanosomiasis is a parasitic disease affecting 5000 humans and millions of livestock animals in sub-Saharan Africa every year. Current treatments are limited, difficult to administer and often toxic causing long term injury or death in many patients. Trypanosome alternative oxidase is a parasite specific enzyme whose inhibition by the natural product ascofuranone (AF) has been shown to be curative in murine models. Until now synthetic methods to AF analogues have been limited, this has restricted both understanding of the key structural features required for binding and also how this chemotype could be developed to an effective therapeutic agent. The development of 3 amenable novel synthetic routes to ascofuranone-like compounds is described. The SAR generated around the AF chemotype is reported with correlation to the inhibition of T. b. brucei growth and corresponding selectivity in cytotoxic assessment in mammalian HepG2 cell lines. These methods allow access to greater synthetic diversification and have enabled the synthesis of compounds that have and will continue to facilitate further optimisation of the AF chemotype into a drug-like lead.

| S-EPMC5697954 | biostudies-literature

Discovery and SAR of Novel Disubstituted Quinazolines as Dual PI3Kalpha/mTOR Inhibitors Targeting Breast Cancer.

Project description:The dual PI3Kα/ m TOR inhibitors represent a promising molecularly targeted therapy for cancer. Here, we documented the discovery of new 2,4-disubstituted quinazoline analogs as potent dual PI3Kα/sm TOR inhibitors. Our structure based chemistry endeavor yielded six excellent compounds 9e, 9f, 9g, 9k, 9m, and 9o with single/double digit nanomolar IC50 values against both enzymes and acceptable aqueous solubility and stability to oxidative metabolism. One of those analogs, 9m, possessed a sulfonamide substituent, which has not been described for this chemical scaffold before. The short direct synthetic routes, structure-activity relationship, in vitro 2D cell culture viability assays against normal fibroblasts and 3 breast cancer cell lines, and in vitro 3D culture viability assay against MCF7 cells for this series are described.

| S-EPMC7667832 | biostudies-literature

Characterizing antiprion compounds based on their binding properties to prion proteins: implications as medical chaperones.

Project description:A variety of antiprion compounds have been reported that are effective in ex vivo and in vivo treatment experiments. However, the molecular mechanisms for most of these compounds remain unknown. Here we classified antiprion mechanisms into four categories: I, specific conformational stabilization; II, nonspecific stabilization; III, aggregation; and IV, interaction with molecules other than PrP(C). To characterize antiprion compounds based on this classification, we determined their binding affinities to PrP(C) using surface plasmon resonance and their binding sites on PrP(C) using NMR spectroscopy. GN8 and GJP49 bound specifically to the hot spot in PrP(C), and acted as "medical chaperones" to stabilize the native conformation. Thus, mechanisms I was predominant. In contrast, quinacrine and epigallocathechin bound to PrP(C) rather nonspecifically; these may stabilize the PrP(C) conformation nonspecifically including the interference with the intermolecular interaction following mechanism II. Congo red and pentosan polysulfate bound to PrP(C) and caused aggregation and precipitation of PrP(C), thus reducing the effective concentration of prion protein. Thus, mechanism III was appropriate. Finally, CP-60, an edarabone derivative, did not bind to PrP(C). Thus these were classified into mechanism IV. However, their antiprion activities were not confirmed in the GT + FK system, whose details remain to be elucidated. This proposed antiprion mechanisms of diverse antiprion compounds could help to elucidate their antiprion activities and facilitate effective antiprion drug discovery.

| S-EPMC3575857 | biostudies-literature

SAR by interligand nuclear overhauser effects (ILOEs) based discovery of acylsulfonamide compounds active against Bcl-x(L) and Mcl-1.

Project description:Overexpression of antiapoptotic members of the Bcl-2 family proteins, such as Bcl-x(L) and Mfl-1, has been shown to be involved in resistance to chemotherapeutic drugs in many forms of cancers. Recent efforts from the Abbott Laboratories resulted in the development of the acylsulfonamide compound and clinical candidate that targets selectively Bcl-2, Bcl-x(L), and Bcl-w while it is not active against Mcl-1 and Bfl-1. However, early clinical and preclinical studies suggest that pan-Bcl-2 antagonists, targeting simultaneously Mcl-1, Bcl-xL, and possibly all other four antiapoptotic Bcl-2 proteins, may result in more efficacious drugs. Here, following an NMR fragment-based approach, SAR by ILOEs, we report on compounds that exhibit nanomolar affinities for both Bcl-x(L) and Mcl-1 in vitro. We believe that these molecules can be used as useful starting point for the development of novel Bcl-2 antagonists, in particular targeting Mcl-1.

| S-EPMC3165075 | 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