6g5j | pdb_00006g5j
Secreted phospholipase A2 type X in complex with ligand
Structural highlights
FunctionPA2GX_HUMAN PA2 catalyzes the calcium-dependent hydrolysis of the 2-acyl groups in 3-sn-phosphoglycerides. Has a powerful potency for releasing arachidonic acid from cell membrane phospholipids. Prefers phosphatidylethanolamine and phosphatidylcholine liposomes to those of phosphatidylserine. Publication Abstract from PubMedA lead generation campaign identified indole-based sPLA2-X inhibitors with a promising selectivity profile against other sPLA2 isoforms. Further optimization of sPLA2 selectivity and metabolic stability resulted in the design of (-)-17, a novel, potent, and selective sPLA2-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(-/-) murine model of atherosclerosis to evaluate the effect of reversible, pharmacological sPLA2-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. Design of Selective sPLA2-X Inhibitor (-)-2-{2-[Carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl]pyridine-2-yl}propanoic Acid.,Giordanetto F, Knerr L, Nordberg P, Pettersen D, Selmi N, Beisel HG, de la Motte H, Mansson A, Dahlstrom M, Broddefalk J, Saarinen G, Klingegard F, Hurt-Camejo E, Rosengren B, Wikstrom J, Wagberg M, Brengdahl J, Rohman M, Sandmark J, Akerud T, Roth RG, Jansen F, Ahlqvist M ACS Med Chem Lett. 2018 Jun 23;9(7):600-605. doi: 10.1021/acsmedchemlett.7b00507., eCollection 2018 Jul 12. PMID:30034586[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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