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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 ...

  • 2018-06-23
  • American Chemical Society,2018
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:ri-37293
  • https://urn.kb.se/resolve?urn=urn:nbn:se:ri:diva-37293URI
  • https://doi.org/10.1021/acsmedchemlett.7b00507DOI

Supplementary language notes

  • Language:English
  • Summary in:English

Part of subdatabase

Classification

  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Funding details: AstraZeneca
  • 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

  • TEKNIK OCH TEKNOLOGIER Kemiteknik hsv//swe
  • ENGINEERING AND TECHNOLOGY Chemical Engineering hsv//eng
  • 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

Added entries (persons, corporate bodies, meetings, titles ...)

  • Knerr, LaurentAstraZeneca, Sweden (author)
  • Nordberg, Peter A.AstraZeneca, Sweden (author)
  • Pettersen, DanielAstraZeneca, Sweden (author)
  • Selmi, NidhalAstraZeneca, Sweden (author)
  • Beisel, Hans GeorgAstraZeneca, Sweden; Medivir AB, Sweden (author)
  • de la Motte, Hanna (author)
  • Månsson, ÅsaAstraZeneca, Sweden; Alfa Laval AB, Sweden (author)
  • Dahlström, MikaelAstraZeneca, Sweden (author)
  • Broddefalk, JohanAstraZeneca, Sweden (author)
  • Saarinen, GabrielleAstraZeneca, Sweden; SCA Hygiene Products AB, Sweden (author)
  • Klingegård, FredrikAstraZeneca, Sweden; SciLifeLab, Sweden (author)
  • Hurt-Camejo, EvaAstraZeneca, Sweden (author)
  • Rosengren, BirgittaAstraZeneca, Sweden (author)
  • Wikström, JohannesAstraZeneca, Sweden (author)
  • Wågberg, MariaAstraZeneca, Sweden (author)
  • Brengdahl, JohanAstraZeneca, Sweden (author)
  • Rohman, MattiasAstraZeneca, Sweden (author)
  • Sandmark, JennyAstraZeneca, Sweden (author)
  • Åkerud, TomasAstraZeneca, Sweden (author)
  • Roth, Robert G.AstraZeneca, Sweden (author)
  • Jansen, FrankAstraZeneca, Sweden (author)
  • Ahlqvist, MarieAstraZeneca, Sweden (author)
  • AstraZeneca, Sweden; Shaw Research, USAAstraZeneca, Sweden (creator_code:org_t)

Related titles

  • In:ACS Medicinal Chemistry Letters: American Chemical Society9:7, s. 600-6051948-5875

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