Identification of highly potent and selective HTRA1 inhibitors.
Bioorg Med Chem Lett
; 109: 129814, 2024 Sep 01.
Article
in En
| MEDLINE
| ID: mdl-38815872
ABSTRACT
High temperature requirement A serine peptidase 1 (HTRA1) is a serine protease involved in an array of signaling pathways. It is also responsible for the regulation of protein aggregates via refolding, translocation, and degradation. It has subsequently been found that runaway proteolytic HTRA1 activity plays a role in a variety of diseases, including Age-Related Macular Degeneration (AMD), osteoarthritis, and Rheumatoid Arthritis. Selective inhibition of serine protease HTRA1 therefore offers a promising new strategy for the treatment of these diseases. Herein we disclose structure-activity-relationship (SAR) studies which identify key interactions responsible for binding affinity of small molecule inhibitors to HTRA1. The study results in highly potent molecules with IC50's less than 15 nM and excellent selectivity following a screen of 35 proteases.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Serine Endopeptidases
/
High-Temperature Requirement A Serine Peptidase 1
Limits:
Humans
Language:
En
Journal:
Bioorg Med Chem Lett
/
Bioorg. med. chem. lett
/
Bioorganic & medicinal chemistry letters
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2024
Document type:
Article
Affiliation country:
Estados Unidos
Country of publication:
Reino Unido