Optimization of Physicochemical Properties and ADME for 2,4-Substituted 1<i>H</i>-Pyrrolo[2,3<i>b</i>]pyridines Inhibitors of Trypanosome Proliferation
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 <b>18a,</b> 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.
Authors
- Erica Penn
- Kelly A. Bachovchin
- Gloria Ceballos-Pérez (ORCID: https://orcid.org/0000-0002-6012-9995)
- Guiomar Pérez‐Moreno (ORCID: https://orcid.org/0000-0002-6892-6083)
- Baljinder Singh (ORCID: https://orcid.org/0000-0003-2828-5768)
- Pilar Manzano-Chinchon
- Dolores González‐Pacanowska (ORCID: https://orcid.org/0000-0002-4303-5209)
- Richard J. Sciotti (ORCID: https://orcid.org/0000-0002-3069-3122)
- Miguel Navarro (ORCID: https://orcid.org/0000-0003-2301-2699)
- Lori Ferrins (ORCID: https://orcid.org/0000-0001-8992-0919)
- Michael P. Pollastri (ORCID: https://orcid.org/0000-0001-9943-7197)
- Maria Santos Martínez (ORCID: https://orcid.org/0000-0001-7894-2135)
- Cristina Bosch‐Navarrete (ORCID: https://orcid.org/0000-0002-6064-0064)
- Raquel García‐Hernández (ORCID: https://orcid.org/0000-0001-9997-6051)
- Norma Roncal
- Domingo I. Rojas-Barros (ORCID: https://orcid.org/0000-0001-8625-2564)
- Rosario Díaz-González (ORCID: https://orcid.org/0000-0002-3187-2704)
- Mitch Rivers
- Robert F. Campbell (ORCID: https://orcid.org/0000-0002-8745-2805)
- Luis M. Ruiz‐Pérez (ORCID: https://orcid.org/0000-0001-7681-4471)
Institutions
- Northeastern University (US)
- GlaxoSmithKline (France) (FR)
- Instituto de Parasitología y Biomedicina "López - Neyra" (ES)
- GMV Innovating Solutions (Spain) (ES)
- Universidad del Noreste (MX)
- Walter Reed Army Institute of Research (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-09-20
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01217
- Primary Topic
- Synthesis and Biological Evaluation
- Type
- article
- Field-Weighted Citation Impact
- 0.00