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Design of Selective...
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Giordanetto, FabrizioAstraZeneca, Sweden; Shaw Research, USA
(author)
Design of Selective sPLA2-X Inhibitor (-)-2-{2-[Carbamoyl-6-(trifluoromethoxy)-1 H-indol-1-yl]pyridine-2-yl}propanoic Acid
- Article/chapterEnglish2018
Publisher, publication year, extent ...
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2018-06-23
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American Chemical Society,2018
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printrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:ri-37293
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https://urn.kb.se/resolve?urn=urn:nbn:se:ri:diva-37293URI
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https://doi.org/10.1021/acsmedchemlett.7b00507DOI
Supplementary language notes
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Language:English
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Summary in:English
Part of subdatabase
Classification
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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Funding details: AstraZeneca
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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.
Subject headings and genre
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TEKNIK OCH TEKNOLOGIER Kemiteknik hsv//swe
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ENGINEERING AND TECHNOLOGY Chemical Engineering hsv//eng
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atherosclerosis
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carotid ligation
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coronary artery disease
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inhibitor
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Secreted phospholipase A2 type X
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sPLA2-X
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2 [2 [carbamoyl 6 (trifluoromethoxy) 1h indol 1 yl]pyridine 2 yl]propanoic Acid
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propionic acid derivative
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unclassified drug
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animal experiment
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animal model
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Article
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carotid artery ligation
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controlled study
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drug absorption
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drug bioavailability
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drug clearance
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drug design
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drug potency
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drug selectivity
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IC50
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IC90
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in vitro study
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in vivo study
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lipophilicity
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male
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mouse
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nonhuman
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plasma protein binding
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priority journal
Added entries (persons, corporate bodies, meetings, titles ...)
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Knerr, LaurentAstraZeneca, Sweden
(author)
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Nordberg, Peter A.AstraZeneca, Sweden
(author)
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Pettersen, DanielAstraZeneca, Sweden
(author)
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Selmi, NidhalAstraZeneca, Sweden
(author)
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Beisel, Hans GeorgAstraZeneca, Sweden; Medivir AB, Sweden
(author)
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de la Motte, Hanna
(author)
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Månsson, ÅsaAstraZeneca, Sweden; Alfa Laval AB, Sweden
(author)
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Dahlström, MikaelAstraZeneca, Sweden
(author)
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Broddefalk, JohanAstraZeneca, Sweden
(author)
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Saarinen, GabrielleAstraZeneca, Sweden; SCA Hygiene Products AB, Sweden
(author)
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Klingegård, FredrikAstraZeneca, Sweden; SciLifeLab, Sweden
(author)
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Hurt-Camejo, EvaAstraZeneca, Sweden
(author)
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Rosengren, BirgittaAstraZeneca, Sweden
(author)
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Wikström, JohannesAstraZeneca, Sweden
(author)
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Wågberg, MariaAstraZeneca, Sweden
(author)
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Brengdahl, JohanAstraZeneca, Sweden
(author)
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Rohman, MattiasAstraZeneca, Sweden
(author)
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Sandmark, JennyAstraZeneca, Sweden
(author)
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Åkerud, TomasAstraZeneca, Sweden
(author)
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Roth, Robert G.AstraZeneca, Sweden
(author)
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Jansen, FrankAstraZeneca, Sweden
(author)
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Ahlqvist, MarieAstraZeneca, Sweden
(author)
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AstraZeneca, Sweden; Shaw Research, USAAstraZeneca, Sweden
(creator_code:org_t)
Related titles
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In:ACS Medicinal Chemistry Letters: American Chemical Society9:7, s. 600-6051948-5875
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de la Motte, Han ...
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Månsson, Åsa
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Hurt-Camejo, Eva
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Rosengren, Birgi ...
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Brengdahl, Johan
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Roth, Robert G.
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