Optimization of Physicochemical Properties and ADME for 2,4-Substituted 1 H -Pyrrolo[2,3 b ]pyridines Inhibitors of Trypanosome Proliferation
Year: 2025
Type: article
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.
Source: Journal of Medicinal Chemistry
Authors: Kelly A. Bachovchin, Rosario Díaz, Gloria Ceballos-Perez, Domingo Rojas-Barros, Guiomar Pérez-Moreno, Raquel García-Hernández, Cristina Bosch-Navarrete, Mitch Rivers, Erica C. Penn, Norma E. Roncal, Richard J. Sciotti, Robert F. Campbell, Maria Santos Martinez-Martinez, Pilar Manzano-Chinchon, Luis Miguel Ruiz-Perez, Miguel Navarro, Dolores González-Pacanowska, Michael P. Pollastri, Lori Ferrins, Baljinder Singh
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Funders: Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Ministerio de Economía y Competitividad, Red de Investigación Cooperativa en Enfermedades Tropicales, Agencia Estatal de Investigación, National Institute of Allergy and Infectious Diseases, NHLBI Division of Intramural Research
OpenAlex ID: W4414372107