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

Autor:	Fiona S. Lucas, Anthony William James Cooper, Ed Robinson, Ian Robert Baldwin, Charlotte J. Hardy, Giovanni Vitulli, Suzanne Elaine Keeling, Daniel Thomas, Joelle Le, Christopher James Lunniss, Sarah Smith, Zoe Alicia Harrison, Angela M. Deakin, Augustin Amour, Stefano Livia, Stephen Barry Guntrip, Yoshiaki Washio, Leigh M. Felton, Katherine Louise Jones, Nigel J. Parr, Kenneth David Down, Paul Jones, J. Nicole Hamblin, Paul Rowland
Rok vydání:	2015
Předmět:	Gene isoform Male Indazoles Indoles Ovalbumin Respiratory Tract Diseases Pharmacology Isozyme Piperazines Rats Sprague-Dawley chemistry.chemical_compound Pulmonary Disease Chronic Obstructive Structure-Activity Relationship Th2 Cells Microsomes Drug Discovery Administration Inhalation medicine Structure–activity relationship Potency Animals Humans Respiratory system Oxazoles Phosphoinositide-3 Kinase Inhibitors Sulfonamides Phosphoinositide 3-kinase biology Chemistry Respiratory disease Stereoisomerism Pneumonia medicine.disease Asthma Rats Isoenzymes Molecular Docking Simulation biology.protein Molecular Medicine Female Rabbits Lead compound
Zdroj:	Journal of medicinal chemistry. 58(18)
ISSN:	1520-4804
Popis:	Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3f87d4bbb39df1904e25ad08de8b274b https://pubmed.ncbi.nlm.nih.gov/26301626 Zobrazit plný text záznamu