| Literature DB >> 34156862 |
Dana M Klug1, Eftychia M Mavrogiannaki1, Katherine C Forbes1, Lisseth Silva1, Rosario Diaz-Gonzalez2, Guiomar Pérez-Moreno2, Gloria Ceballos-Pérez2, Raquel Garcia-Hernández2, Cristina Bosch-Navarrete2, Carlos Cordón-Obras2, Claudia Gómez-Liñán2, Andreu Saura2, Jeremiah D Momper3, Maria Santos Martinez-Martinez4, Pilar Manzano4, Ali Syed3, Nelly El-Sakkary3, Conor R Caffrey3, Francisco Gamarro2, Luis Miguel Ruiz-Perez2, Dolores Gonzalez Pacanowska2, Lori Ferrins1, Miguel Navarro2, Michael P Pollastri1.
Abstract
Neglected tropical diseases such as human African trypanosomiasis (HAT) are prevalent primarily in tropical climates and among populations living in poverty. Historically, the lack of economic incentive to develop new treatments for these diseases has meant that existing therapeutics have serious shortcomings in terms of safety, efficacy, and administration, and better therapeutics are needed. We now report a series of 3,5-disubstituted-7-azaindoles identified as growth inhibitors of Trypanosoma brucei, the parasite that causes HAT, through a high-throughput screen. We describe the hit-to-lead optimization of this series and the development and preclinical investigation of 29d, a potent antitrypanosomal compound with promising pharmacokinetic (PK) parameters. This compound was ultimately not progressed beyond in vivo PK studies due to its inability to penetrate the blood-brain barrier (BBB), critical for stage 2 HAT treatments.Entities:
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Year: 2021 PMID： 34156862 PMCID： PMC8412142 DOI： 10.1021/acs.jmedchem.1c00674
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 8.039