Improvement of Aqueous Solubility of Lapatinib-Derived Analogues: Identification of a Quinolinimine Lead for Human African Trypanosomiasis Drug Development.
Animals
Blood Proteins
/ chemistry
Disease Models, Animal
Drug Design
Drug Evaluation, Preclinical
Half-Life
Hepatocytes
/ cytology
Humans
Lapatinib
/ analogs & derivatives
Mice
Microsomes, Liver
Quinazolines
/ chemistry
Rats
Solubility
Structure-Activity Relationship
Thermodynamics
Trypanocidal Agents
/ chemistry
Trypanosoma brucei brucei
/ drug effects
Trypanosomiasis, African
/ drug therapy
Water
/ chemistry
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
24 01 2019
24 01 2019
Historique:
pubmed:
20
12
2018
medline:
29
10
2019
entrez:
20
12
2018
Statut:
ppublish
Résumé
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 (CEC
Identifiants
pubmed: 30565932
doi: 10.1021/acs.jmedchem.8b01365
pmc: PMC6556231
mid: NIHMS1032841
doi:
Substances chimiques
Blood Proteins
0
Quinazolines
0
Trypanocidal Agents
0
Water
059QF0KO0R
Lapatinib
0VUA21238F
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
665-687Subventions
Organisme : NIAID NIH HHS
ID : R01 AI082577
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI124046
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI127594
Pays : United States
Organisme : NIAID NIH HHS
ID : R56 AI099476
Pays : United States
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