1. Improvement of Aqueous Solubility of Lapatinib-Derived Analogues: Identification of a Quinolinimine Lead for Human African Trypanosomiasis Drug Development
- Author
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Bachovchin, Kelly A, Sharma, Amrita, Bag, Seema, Klug, Dana M, Schneider, Katherine M, Singh, Baljinder, Jalani, Hitesh B, Buskes, Melissa J, Mehta, Naimee, Tanghe, Scott, Momper, Jeremiah D, Sciotti, Richard J, Rodriguez, Ana, Mensa-Wilmot, Kojo, Pollastri, Michael P, and Ferrins, Lori
- Subjects
Rare Diseases ,Orphan Drug ,Vector-Borne Diseases ,Infectious Diseases ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Good Health and Well Being ,Animals ,Blood Proteins ,Disease Models ,Animal ,Drug Design ,Drug Evaluation ,Preclinical ,Half-Life ,Hepatocytes ,Humans ,Lapatinib ,Mice ,Microsomes ,Liver ,Quinazolines ,Rats ,Solubility ,Structure-Activity Relationship ,Thermodynamics ,Trypanocidal Agents ,Trypanosoma brucei brucei ,Trypanosomiasis ,African ,Water ,Medicinal and Biomolecular Chemistry ,Organic Chemistry ,Pharmacology and Pharmaceutical Sciences ,Medicinal & Biomolecular Chemistry - Abstract
Lapatinib, an approved epidermal growth factor receptor inhibitor, was explored as a starting point for the synthesis of new hits against Trypanosoma brucei, the causative agent of human African trypanosomiasis (HAT). Previous work culminated in 1 (NEU-1953), which was part of a series typically associated with poor aqueous solubility. In this report, we present various medicinal chemistry strategies that were used to increase the aqueous solubility and improve the physicochemical profile without sacrificing antitrypanosomal potency. To rank trypanocidal hits, a new assay (summarized in a cytocidal effective concentration (CEC50)) was established, as part of the lead selection process. Increasing the sp3 carbon content of 1 resulted in 10e (0.19 μM EC50 against T. brucei and 990 μM aqueous solubility). Further chemical exploration of 10e yielded 22a, a trypanocidal quinolinimine (EC50: 0.013 μM; aqueous solubility: 880 μM; and CEC50: 0.18 μM). Compound 22a reduced parasitemia 109 fold in trypanosome-infected mice; it is an advanced lead for HAT drug development.
- Published
- 2019