Optimizing a Weakly Binding Fragment into a Potent RORγt Inverse Agonist with Efficacy in an in Vivo Inflammation Model.
J Med Chem
; 61(15): 6724-6735, 2018 08 09.
Article
in En
| MEDLINE
| ID: mdl-29990434
ABSTRACT
The transcription factor RORγt is an attractive drug-target due to its role in the differentiation of IL-17 producing Th17 cells that play a critical role in the etiopathology of several autoimmune diseases. Identification of starting points for RORγt inverse agonists with good properties has been a challenge. We report the identification of a fragment hit and its conversion into a potent inverse agonist through fragment optimization, growing and merging efforts. Further analysis of the binding mode revealed that inverse agonism was achieved by an unusual mechanism. In contrast to other reported inverse agonists, there is no direct interaction or displacement of helix 12 observed in the crystal structure. Nevertheless, compound 9 proved to be efficacious in a delayed-type hypersensitivity (DTH) inflammation model in rats.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Drug Inverse Agonism
/
Drug Discovery
/
Nuclear Receptor Subfamily 1, Group F, Member 3
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2018
Document type:
Article