ArticleJournal of medicinal chemistry2014
Lead optimization of a pyrazole sulfonamide series of Trypanosoma brucei N-myristoyltransferase inhibitors: identification and evaluation of CNS penetrant compounds as potential treatments for stage 2 human African trypanosomiasis.
Article in Journal of medicinal chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 73 citations in OpenAlex.
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- Preparation, separation and storage of N-monofluoromethyl amides and carbamates.Nature chemistry · 2025Article
- Transforming the chemotherapy of human African trypanosomiasis.Clinical microbiology reviews · 2025Review
- AttenhERG: a reliable and interpretable graph neural network framework for predicting hERG channel blockers.Journal of cheminformatics · 2024Article
- Aminopyridines in the development of drug candidates against protozoan neglected tropical diseases.Future medicinal chemistry · 2024Review
- Tackling Sleeping Sickness: Current and Promising Therapeutics and Treatment Strategies.International journal of molecular sciences · 2023Review
- Article
- Plant Terpenoids as Hit Compounds against Trypanosomiasis.Pharmaceuticals (Basel, Switzerland) · 2022Review
- QSAR and Pharmacophore Modeling of Nitrogen Heterocycles as Potent HumanMolecules (Basel, Switzerland) · 2021Article
- N-myristoyltransferase proteins in breast cancer: prognostic relevance and validation as a new drug target.Breast cancer research and treatment · 2021Article
- Targeting N-myristoylation for therapy of B-cell lymphomas.Nature communications · 2020Article
- Wheat pathogenRSC chemical biology · 2020Article
- Exploring NovelACS omega · 2019Article
- Validation and Invalidation of Chemical Probes for the Human N-myristoyltransferases.Cell chemical biology · 2019Article
- Pharmacological Validation of N-Myristoyltransferase as a Drug Target in Leishmania donovani.ACS infectious diseases · 2019Article
- A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors.Journal of medicinal chemistry · 2018Article
- Design and Synthesis of Brain Penetrant Trypanocidal N-Myristoyltransferase Inhibitors.Journal of medicinal chemistry · 2017Article
- Novel lead compounds in pre-clinical development against African sleeping sickness.MedChemComm · 2017Review
- Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need.Nature reviews. Microbiology · 2017Review
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Authors and funding
21 authors at 1 institution in 2 countries.
Funding
Abstract
Trypanosoma brucei N-myristoyltransferase (TbNMT) is an attractive therapeutic target for the treatment of human African trypanosomiasis (HAT). From previous studies, we identified pyrazole sulfonamide, DDD85646 (1), a potent inhibitor of TbNMT. Although this compound represents an excellent lead, poor central nervous system (CNS) exposure restricts its use to the hemolymphatic form (stage 1) of the disease. With a clear clinical need for new drug treatments for HAT that address both the hemolymphatic and CNS stages of the disease, a chemistry campaign was initiated to address the shortfalls of this series. This paper describes modifications to the pyrazole sulfonamides which markedly improved blood-brain barrier permeability, achieved by reducing polar surface area and capping the sulfonamide. Moreover, replacing the core aromatic with a flexible linker significantly improved selectivity. This led to the discovery of DDD100097 (40) which demonstrated partial efficacy in a stage 2 (CNS) mouse model of HAT.
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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.