2. Academic Validation
  3. Optimization of Physicochemical Properties and ADME for 2,4-Substituted 1 H-Pyrrolo[2,3 b]pyridines Inhibitors of Trypanosome Proliferation

Optimization of Physicochemical Properties and ADME for 2,4-Substituted 1 H-Pyrrolo[2,3 b]pyridines Inhibitors of Trypanosome Proliferation

  • J Med Chem. 2025 Oct 9;68(19):20154-20179. doi: 10.1021/acs.jmedchem.5c01217.
Kelly A Bachovchin 1,  Rosario Díaz 2,  Gloria Ceballos-Perez 2,  Domingo Rojas-Barros 2,  Guiomar Pérez-Moreno 2,  Raquel García-Hernández 2,  Cristina Bosch-Navarrete 2,  Mitch Rivers 1,  Erica C Penn 3,  Norma E Roncal 3,  Richard J Sciotti 3,  Robert F Campbell 3,  Maria Santos Martinez-Martinez 4,  Pilar Manzano-Chinchon 4,  Luis Miguel Ruiz-Perez 2,  Miguel Navarro 2,  Dolores González-Pacanowska 2,  Michael P Pollastri 1,  Lori Ferrins 1 5,  Baljinder Singh 1
Affiliations

Affiliations

  • 1 Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States.
  • 2 Instituto de Parasitología y Biomedicina ''López-Neyra'' Consejo Superior de Investigaciones Científicas (CSIC), Granada 18016, Spain.
  • 3 Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.
  • 4 Global Health Medicines R&D, GSK, Tres Cantos, Madrid 28760, Spain.
  • 5 Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts 02115, United States.
PMID: 40974321 DOI: 10.1021/acs.jmedchem.5c01217
Abstract

Neglected tropical diseases, such as human African trypanosomiasis (HAT), require novel treatments that can populate the clinical pipeline in the event of rising resistance and treatment recrudescence. Following a high-throughput screen of almost 42,000 human kinase inhibitor chemotypes, we identified a 2,4-disubstituted azaindole that had good antiparasitic activity, selectivity, and predicted brain exposure, but that failed to meet our criteria for advancement into an efficacy study. Following hit-to-lead optimization, we arrived at 18a, which offered the best combination of potency, properties, and pharmacokinetic parameters, and, while not curative, this work leads to opportunities for continued optimization for HAT and cutaneous leishmaniasis.

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