Medicinal Chemistry Optimization of a Diaminopurine Chemotype: Toward a Lead for Trypanosoma brucei Inhibitors
| العنوان: | Medicinal Chemistry Optimization of a Diaminopurine Chemotype: Toward a Lead for Trypanosoma brucei Inhibitors |
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| المؤلفون: | Pilar Manzano, Maria Santos Martinez-Martinez, Miguel Navarro, Michael P. Pollastri, Naresh Gunaganti, Gloria Ceballos-Pérez, Kirsten Gillingwater, Domingo I. Rojas-Barros, Rosario Diaz-Gonzalez, Baljinder Singh |
| المساهمون: | Tres Cantos Open Lab Foundation, National Institute of Allergy and Infectious Diseases (US), National Institutes of Health (US) |
| المصدر: | Digital.CSIC. Repositorio Institucional del CSIC instname J Med Chem |
| بيانات النشر: | American Chemical Society (ACS), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Antiparasitic, medicine.drug_class, Trypanosoma brucei brucei, Trypanosoma brucei, Proof of Concept Study, Medicinal chemistry, Article, Mice, Structure-Activity Relationship, Parasitic Sensitivity Tests, In vivo, parasitic diseases, Drug Discovery, medicine, Animals, Humans, Structure–activity relationship, African trypanosomiasis, ADME, Molecular Structure, Chemotype, biology, Chemistry, Hep G2 Cells, biology.organism_classification, medicine.disease, Trypanocidal Agents, In vitro, Rats, Purines, Microsomes, Liver, Molecular Medicine |
| الوصف: | Human African trypanosomiasis (HAT), or sleeping sickness, is caused by the protozoan parasite Trypanosoma brucei and transmitted through the bite of infected tsetse flies. The disease is considered fatal if left untreated. To identify new chemotypes against Trypanosoma brucei, previously we identified 797 potent kinase-targeting inhibitors grouped into 59 clusters plus 53 singleton compounds with at least 100-fold selectivity over HepG2 cells. From this set of hits, a cluster of diaminopurine-derived compounds was identified. Herein, we report our medicinal chemistry investigation involving the exploration of structure¿activity and structure¿property relationships around one of the high-throughput screening (HTS) hits, N2-(thiophen-3-yl)-N6-(2,2,2-trifluoroethyl)-9H-purine-2,6-diamine (1, NEU-1106). This work led to the identification of a potent lead compound (4aa, NEU-4854) with improved in vitro absorption, distribution, metabolism, and excretion (ADME) properties, which was progressed into proof-of-concept translation of in vitro antiparasitic activity to in vivo efficacy. The authors are grateful to David Swinney (iRND3, forTbMAPK6 experiment), AstraZeneca (for in vitro ADMEexperiments), Charles River Lab (for cell permeability, mouseliver microsome stability, and CYP enzyme studies), andGlaxoSmithKline (forin vivopharmacokinetics experiments).This work was supported by the Tres Cantos Open LabFoundation and the National Institute of Allergy and InfectiousDiseases (R01AI114685; R01AI126311; R01AI124046; andR01AI104576). All animal studies were ethically reviewed andcarried out in accordance with Animals (Scientific Procedures)Act 1986; and the CSIC and GSK Policy on the Care, Welfare,and Treatment of Animals. We certify that the research usingeach of the HBS marked above was conducted according to therequirements of POL-GSKF-410 and associated relevant SOPsand that all related documentation is stored in an approvedHBSM database. |
| تدمد: | 1520-4804 0022-2623 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0a8b3af0fa2337d349ba09302701f4b6 https://doi.org/10.1021/acs.jmedchem.0c01017 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....0a8b3af0fa2337d349ba09302701f4b6 |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15204804 00222623 |
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