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Design of Selective sPLA2-X Inhibitor (-)-2-{2-[Carbamoyl-6-(trifluoromethoxy)-1 H-indol-1-yl]pyridine-2-yl}propanoic Acid
AstraZeneca, Sweden; Shaw Research, USA.
AstraZeneca, Sweden.
AstraZeneca, Sweden.
AstraZeneca, Sweden.
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2018 (English)In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 9, no 7, p. 600-605Article in journal (Refereed) Published
Abstract [en]

A 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.

Place, publisher, year, edition, pages
American Chemical Society , 2018. Vol. 9, no 7, p. 600-605
Keywords [en]
atherosclerosis, carotid ligation, coronary artery disease, inhibitor, Secreted phospholipase A2 type X, sPLA2-X, 2 [2 [carbamoyl 6 (trifluoromethoxy) 1h indol 1 yl]pyridine 2 yl]propanoic Acid, propionic acid derivative, unclassified drug, animal experiment, animal model, Article, carotid artery ligation, controlled study, drug absorption, drug bioavailability, drug clearance, drug design, drug potency, drug selectivity, IC50, IC90, in vitro study, in vivo study, lipophilicity, male, mouse, nonhuman, plasma protein binding, priority journal
National Category
Chemical Engineering
Identifiers
URN: urn:nbn:se:ri:diva-37293DOI: 10.1021/acsmedchemlett.7b00507Scopus ID: 2-s2.0-85049247977OAI: oai:DiVA.org:ri-37293DiVA, id: diva2:1280251
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Funding details: AstraZeneca

Available from: 2019-01-18 Created: 2019-01-18 Last updated: 2019-03-28Bibliographically approved

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de la Motte, Hanna

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