Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3-Kinase delta for the Treatment of Respiratory Disease

Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3K delta potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (G5K2292767) for the treatment of respiratory indications via inhalatio...

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Veröffentlicht in:Journal of medicinal chemistry Jg. 58; H. 18; S. 7381 - 7399
Hauptverfasser: Down, Kenneth, Amour, Augustin, Baldwin, Ian R., Cooper, Anthony W. J., Deakin, Angela M., Felton, Leigh M., Guntrip, Stephen B., Hardy, Charlotte, Harrison, Zoe A., Jones, Katherine L., Jones, Paul, Keeling, Suzanne E., Le, Joelle, Livia, Stefano, Lucas, Fiona, Lunniss, Christopher J., Parr, Nigel J., Robinson, Ed, Rowland, Paul, Smith, Sarah, Thomas, Daniel A., Vitulli, Giovanni, Washio, Yoshiaki, Hamblin, J. Nicole
Format: Journal Article
Sprache:Englisch
Veröffentlicht: WASHINGTON Amer Chemical Soc 24.09.2015
Schlagworte:
Administration, Inhalation
Animals
Asthma - drug therapy
Chemistry, Medicinal
Female
Humans
Indazoles - chemistry
Indazoles - pharmacokinetics
Indazoles - pharmacology
Isoenzymes - antagonists & inhibitors
Life Sciences & Biomedicine
Male
Microsomes - metabolism
Molecular Docking Simulation
Ovalbumin - immunology
Oxazoles - chemistry
Oxazoles - pharmacokinetics
Oxazoles - pharmacology
Pharmacology & Pharmacy
Phosphoinositide-3 Kinase Inhibitors
Pneumonia - drug therapy
Pneumonia - immunology
Pulmonary Disease, Chronic Obstructive - drug therapy
Rabbits
Rats
Rats, Sprague-Dawley
Respiratory Tract Diseases - drug therapy
Science & Technology
Stereoisomerism
Structure-Activity Relationship
Sulfonamides - chemistry
Sulfonamides - pharmacokinetics
Sulfonamides - pharmacology
Th2 Cells - immunology
BLOCKERS
MECHANISMS
PI3K
PATHWAY
DISCOVERY
ISSN:0022-2623, 1520-4804
Online-Zugang:Weitere Angaben
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Beschreibung
Zusammenfassung:Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3K delta potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (G5K2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3K delta over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.5b00767