Stereochemical Differences in Fluorocyclopropyl Amides Enable Tuning of Btk Inhibition and Off-Target Activity.
Journal
ACS medicinal chemistry letters
ISSN: 1948-5875
Titre abrégé: ACS Med Chem Lett
Pays: United States
ID NLM: 101521073
Informations de publication
Date de publication:
13 Aug 2020
13 Aug 2020
Historique:
received:
13
05
2020
accepted:
13
07
2020
entrez:
25
8
2020
pubmed:
25
8
2020
medline:
25
8
2020
Statut:
epublish
Résumé
Bruton's tyrosine kinase (Btk) is thought to play a pathogenic role in chronic immune diseases such as rheumatoid arthritis and lupus. While covalent, irreversible Btk inhibitors are approved for treatment of hematologic malignancies, they are not approved for autoimmune indications. In efforts to develop additional series of reversible Btk inhibitors for chronic immune diseases, we sought to differentiate from our clinical stage inhibitor fenebrutinib using cyclopropyl amide isosteres of the 2-aminopyridyl group to occupy the flat, lipophilic H2 pocket. While drug-like properties were retained-and in some cases improved-a safety liability in the form of hERG inhibition was observed. When a fluorocyclopropyl amide was incorporated, Btk and off-target activity was found to be stereodependent and a lead compound was identified in the form of the (
Identifiants
pubmed: 32832028
doi: 10.1021/acsmedchemlett.0c00249
pmc: PMC7430973
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1588-1597Informations de copyright
Copyright © 2020 American Chemical Society.
Déclaration de conflit d'intérêts
The authors declare the following competing financial interest(s): The authors are, or were, employees of Genentech/Roche and hold/have held shares in Roche.
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