Identification of highly potent and selective HTRA1 inhibitors.

Autor: Dennis DG; Medicinal Chemistry Knowledge Center, Sarafan ChEM-H, Stanford University, CA 94305, USA; Molecular Surgery Laboratory, Byers Eye Institute, Department of Ophthalmology, Stanford University, CA 94304, USA., Joo Sun Y; Molecular Surgery Laboratory, Byers Eye Institute, Department of Ophthalmology, Stanford University, CA 94304, USA., Parsons DE; Medicinal Chemistry Knowledge Center, Sarafan ChEM-H, Stanford University, CA 94305, USA; Molecular Surgery Laboratory, Byers Eye Institute, Department of Ophthalmology, Stanford University, CA 94304, USA., Mahajan VB; Molecular Surgery Laboratory, Byers Eye Institute, Department of Ophthalmology, Stanford University, CA 94304, USA; Veterans Affairs Palo Alto Health Care System, CA 94304, USA. Electronic address: vinit.mahajan@stanford.com., Smith M; Medicinal Chemistry Knowledge Center, Sarafan ChEM-H, Stanford University, CA 94305, USA. Electronic address: mxsmith@stanford.edu.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2024 Sep 01; Vol. 109, pp. 129814. Date of Electronic Publication: 2024 May 28.
DOI: 10.1016/j.bmcl.2024.129814
Abstrakt: 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 IC 50 's less than 15 nM and excellent selectivity following a screen of 35 proteases.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: David Dennis reports financial support was provided by National Institutes of Health. Mark Smith reports a relationship with Riboscience LLC that includes: consulting or advisory and equity or stocks. Mark Smith reports a relationship with Sandbox Group LLC that includes: consulting or advisory. Mark Smith has patent pending to Stanford University. There are no additional relationships to declare If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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