ArticleACS chemical neuroscience2011
Enhancing the Pharmacokinetic Properties of Botulinum Neurotoxin Serotype A Protease Inhibitors Through Rational Design.
Article in ACS chemical neuroscience, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
11 citing papers in PubMed, 19 citations in OpenAlex.
- Identification of Slow-Binding Inhibitors of the BoNT/A Protease.ACS medicinal chemistry letters · 2022Article
- Investigation of thiazolyl-benzothiophenamides as potential agents for African sleeping sickness.RSC medicinal chemistry · 2020Article
- Natural Compounds and Their Analogues as Potent Antidotes against the Most Poisonous Bacterial Toxin.Applied and environmental microbiology · 2018Article
- Epitope targeting of tertiary protein structure enables target-guided synthesis of a potent in-cell inhibitor of botulinum neurotoxin.Angewandte Chemie (International ed. in English) · 2015Article
- SRC family kinase inhibitors antagonize the toxicity of multiple serotypes of botulinum neurotoxin in human embryonic stem cell-derived motor neurons.Neurotoxicity research · 2015Article
- Benzothiophene carboxylate derivatives as novel allosteric inhibitors of branched-chain α-ketoacid dehydrogenase kinase.The Journal of biological chemistry · 2014Article
- Second generation steroidal 4-aminoquinolines are potent, dual-target inhibitors of the botulinum neurotoxin serotype A metalloprotease and P. falciparum malaria.Journal of medicinal chemistry · 2014Article
- Identification of clinically viable quinolinol inhibitors of botulinum neurotoxin A light chain.Journal of medicinal chemistry · 2014Article
- Cargo-delivery platforms for targeted delivery of inhibitor cargos against botulism.Current topics in medicinal chemistry · 2014Review
- A high-throughput-compatible FRET-based platform for identification and characterization of botulinum neurotoxin light chain modulators.Journal of visualized experiments : JoVE · 2013Article
- Reexamining hydroxamate inhibitors of botulinum neurotoxin serotype A: extending towards the β-exosite.Bioorganic & medicinal chemistry letters · 2012Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 4 institutions in 1 country.
Funding
Abstract
Botulinum neurotoxin (BoNT), the etiological agent that causes the neuroparalytic disease botulism, has become a highly studied drug target in light of the potential abuse of this toxin as a weapon of bioterrorism. In particular, small molecule inhibitors of the light chain metalloprotease of BoNT serotype A have received significant attention and a number of small molecule and biologic inhibitors have been reported. However, all small molecules reported have been identified from either primary screens or medicinal chemistry follow-up studies, and the pharmacokinetic profiles of these compounds have not been addressed. In this study, we have removed the pharmacologic liabilities of one of the best compounds reported to date, 2,4-dichlorocinnamate hydroxamic acid, and in the process, uncovered a related class of benzothiophene hydroxamic acids that are significantly more potent inhibitors of the BoNT/A light chain, while also possessing greatly improved ADME properties, with the best compound showing the most potent inhibition of BoNT/A light chain reported (K(i) = 77 nM). Using a strategy of incorporating traditional drug development filters early into the discovery process, potential liabilities in BoNT/A lead compounds have been illuminated and removed, clearing the path for advancement into further pharmacologic optimization and in vivo efficacy testing.
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.