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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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 58; no. 18; pp. 7381 - 7399
Main Authors:	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
Language:	English
Published:	WASHINGTON Amer Chemical Soc 24.09.2015
Subjects:	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
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Summary:	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.
Bibliography:	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