Development of autotaxin inhibitors: A series of tetrazole cinnamides.
Amides
/ chemical synthesis
Animals
Cinnamates
/ chemical synthesis
Dose-Response Relationship, Drug
Drug Development
Enzyme Inhibitors
/ chemical synthesis
Humans
Mice
Models, Molecular
Molecular Structure
Phosphoric Diester Hydrolases
/ metabolism
Rats
Structure-Activity Relationship
Tetrazoles
/ chemical synthesis
Autotaxin inhibition
Clearance
Idiopathic pulmonary fibrosis
PK/PD
hERG inhibition
Journal
Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377
Informations de publication
Date de publication:
01 01 2021
01 01 2021
Historique:
received:
15
09
2020
accepted:
28
10
2020
pubmed:
8
11
2020
medline:
23
7
2021
entrez:
7
11
2020
Statut:
ppublish
Résumé
A series of inhibitors of Autotaxin (ATX) have been developed from a high throughput screening hit, 1a, which shows an alternative binding mode to known catalytic site inhibitors. Selectivity over the hERG channel and microsomal clearance were dependent on the lipophilicity of the compounds, and this was optimised by reduction of clogD whilst maintaining high affinity ATX inhibition. Compound 15a shows good oral exposure, and concentration dependent inhibition of formation of LPA in vivo, as shown in pharmacokinetic-pharmacodynamic (PK/PD) experiments.
Identifiants
pubmed: 33160025
pii: S0960-894X(20)30774-5
doi: 10.1016/j.bmcl.2020.127663
pii:
doi:
Substances chimiques
Amides
0
Cinnamates
0
Enzyme Inhibitors
0
Tetrazoles
0
cinnamic acid
140-10-3
Phosphoric Diester Hydrolases
EC 3.1.4.-
alkylglycerophosphoethanolamine phosphodiesterase
EC 3.1.4.39
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
127663Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.