Design and optimization of a series of 4-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-2-amines: Dual inhibitors of TYK2 and JAK1.
Animals
Arthritis, Experimental
/ drug therapy
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Design
Female
Humans
Janus Kinase 1
/ antagonists & inhibitors
Molecular Structure
Protein Kinase Inhibitors
/ chemical synthesis
Rats
Rats, Inbred Lew
Structure-Activity Relationship
TYK2 Kinase
/ antagonists & inhibitors
Arthritis
Autoimmune
Inflammation
JAK1
Kinase
Psoriasis
TYK2
Journal
Bioorganic & medicinal chemistry
ISSN: 1464-3391
Titre abrégé: Bioorg Med Chem
Pays: England
ID NLM: 9413298
Informations de publication
Date de publication:
15 05 2020
15 05 2020
Historique:
received:
05
02
2020
revised:
25
03
2020
accepted:
27
03
2020
pubmed:
8
4
2020
medline:
2
6
2021
entrez:
8
4
2020
Statut:
ppublish
Résumé
Herein, we disclose a new series of TYK2/ JAK1 inhibitors based upon a 3.1.0 azabicyclic substituted pyrimidine scaffold. We illustrate the use of structure-based drug design for the initial design and subsequent optimization of this series of compounds. One advanced example 19 met program objectives for potency, selectivity and ADME, and demonstrated oral activity in the adjuvant-induced arthritis rat model.
Identifiants
pubmed: 32253095
pii: S0968-0896(20)30301-1
doi: 10.1016/j.bmc.2020.115481
pii:
doi:
Substances chimiques
Protein Kinase Inhibitors
0
JAK1 protein, human
EC 2.7.10.2
Janus Kinase 1
EC 2.7.10.2
TYK2 Kinase
EC 2.7.10.2
TYK2 protein, human
EC 2.7.10.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
115481Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.