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Design of Selective sPLA 2 -X Inhibitor (-)-2-{2-[Carbamoyl-6-(trifluoromethoxy)-1 H -indol-1-yl]pyridine-2-yl}propanoic Acid.
- Source :
-
ACS medicinal chemistry letters [ACS Med Chem Lett] 2018 Jun 23; Vol. 9 (7), pp. 600-605. Date of Electronic Publication: 2018 Jun 23 (Print Publication: 2018). - Publication Year :
- 2018
-
Abstract
- A lead generation campaign identified indole-based sPLA <subscript>2</subscript> -X inhibitors with a promising selectivity profile against other sPLA <subscript>2</subscript> isoforms. Further optimization of sPLA <subscript>2</subscript> selectivity and metabolic stability resulted in the design of (-)- 17 , a novel, potent, and selective sPLA <subscript>2</subscript> -X inhibitor with an exquisite pharmacokinetic profile characterized by high absorption and low clearance, and low toxicological risk. Compound (-)- 17 was tested in an ApoE <superscript>-/-</superscript> murine model of atherosclerosis to evaluate the effect of reversible, pharmacological sPLA <subscript>2</subscript> -X inhibition on atherosclerosis development. Despite being well tolerated and achieving adequate systemic exposure of mechanistic relevance, (-)- 17 did not significantly affect circulating lipid and lipoprotein biomarkers and had no effect on coronary function or histological markers of atherosclerosis.<br />Competing Interests: The authors declare no competing financial interest.
Details
- Language :
- English
- ISSN :
- 1948-5875
- Volume :
- 9
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- ACS medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 30034586
- Full Text :
- https://doi.org/10.1021/acsmedchemlett.7b00507