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2-(4-Chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[H]quinoline-4-carboxylic acid (PSI-697): identification of a clinical candidate from the quinoline salicylic acid series of P-selectin antagonists
- Source :
- Journal of medicinal chemistry. 50(1)
- Publication Year :
- 2007
-
Abstract
- P-selectin-PSGL-1 interaction causes rolling of leukocytes on the endothelial cell surface, which subsequently leads to firm adherence and leukocyte transmigration through the vessel wall into the surrounding tissues. P-selectin is upregulated on the surface of both platelets and endothelium in a variety of atherosclerosis-associated conditions. Consequently, inhibition of this interaction by means of a small molecule P-selectin antagonist is an attractive strategy for the treatment of atherosclerosis. High-throughput screening and subsequent analoging had led to the identification of compound 1 as the lead candidate. Herein, we report the continuation of this work and the discovery of a second-generation series, the tetrahydrobenzoquinoline salicylic acids. These compounds have improved pharmacokinetic properties, and a number of them have shown oral efficacy in mouse and rat models of atherogenesis and vascular injury. The lead 31 (PSI-697), is currently in clinical development for the treatment of atherothrombotic vascular events.
- Subjects :
- Male
Indoles
Endothelium
P-selectin
Carboxylic acid
Administration, Oral
Rats, Sprague-Dawley
chemistry.chemical_compound
Mice
Structure-Activity Relationship
Apolipoproteins E
Dogs
Fibrinolytic Agents
In vivo
Drug Discovery
medicine
Animals
Carotid Stenosis
Leukocyte Rolling
chemistry.chemical_classification
Mice, Knockout
Quinoline
Atherosclerosis
Small molecule
Salicylates
Rats
Endothelial stem cell
P-Selectin
medicine.anatomical_structure
chemistry
Biochemistry
Hydroxyquinolines
Quinolines
Molecular Medicine
Salicylic acid
Subjects
Details
- ISSN :
- 00222623
- Volume :
- 50
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....1cc2901446f22e4add8ca889571b3870