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PMID: 22437115 Published · ppublish English Journal Article

Identification of a novel series of BET family bromodomain inhibitors: binding mode and profile of I-BET151 (GSK1210151A).

Bioorganic & medicinal chemistry letters ·Vol. 22 ·No. 8 ·2012-04-15 ·Pages 2968-72

Seal J, Lamotte Y, Donche F, Bouillot A, Mirguet O, Gellibert F, Nicodeme E, Krysa G, Kirilovsky J, Beinke S, McCleary S, Rioja I, Bamborough P, Chung CW, Gordon L, Lewis T, Walker AL, Cutler L, Lugo D, Wilson DM, Witherington J, Lee K, Prinjha RK

Abstract

A novel series of quinoline isoxazole BET family bromodomain inhibitors are discussed. Crystallography is used to illustrate binding modes and rationalize their SAR. One member, I-BET151 (GSK1210151A), shows good oral bioavailability in both the rat and minipig as well as demonstrating efficient suppression of bacterial induced inflammation and sepsis in a murine in vivo endotoxaemia model.

MeSH Terms
Animals Binding Sites Crystallography, X-Ray Guinea Pigs Heterocyclic Compounds, 4 or More Rings/chemistry,metabolism Inflammation/drug therapy Isoxazoles/chemical synthesis,chemistry,pharmacology Mice Models, Molecular Nerve Tissue Proteins/antagonists & inhibitors Protein Binding/drug effects Quinolines/chemical synthesis,chemistry,pharmacology Rats
Chemicals
GSK1210151A Heterocyclic Compounds, 4 or More Rings Isoxazoles Nerve Tissue Proteins Quinolines
Authors & Affiliations
23 authors, click to expand affiliations / ORCID
Seal Jonathan
Epinova DPU, GlaxoSmithKline R&D, Medicines Research Centre, Stevenage, Hertfordshire, UK. [email protected]
Lamotte Yann
Donche Frédéric
Bouillot Anne
Mirguet Olivier
Gellibert Françoise
Nicodeme Edwige
Krysa Gael
Kirilovsky Jorge
Beinke Soren
McCleary Scott
Rioja Inma
Bamborough Paul
Chung Chun-Wa
Gordon Laurie
Lewis Toni
Walker Ann L
Cutler Leanne
Lugo David
Wilson David M
Witherington Jason
Lee Kevin
Prinjha Rab K
Article Info
Journal
Bioorganic & medicinal chemistry letters
Abbr.
Bioorg Med Chem Lett
ISSN
1464-3405
DOI
10.1016/j.bmcl.2012.02.041
Email
[email protected]
Published
2012-04-15
Epub
2012-00-24
Pages
2968-72
Language
English
Region
England
NLM ID
9107377
Subset
IM
External Links
PubMed source DOI: 10.1016/j.bmcl.2012.02.041 View journal details
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