Design and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3-Kinase γ (PI3Kγ) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS)

Autor:	Jianglin Liang, Robert J. Davies, James P. Griffith, Hardwin O'dowd, Cameron Stuver Moody, Elaine Krueger, Philip N. Collier, Yusheng Liao, Upul K. Bandarage, Alex Aronov, Jian Wang, Jingrong Cao, Derek B. Lowe, Veronique Damagnez, Elaine Y. Chin, John D. Doran, Emmanuelle Sizensky, Wojciech Dworakowski, Sudipta Mahajan, David D. Deininger, Marc Jacobs, Jinwang Xu, Arnaud Le Tiran, Suvarna Khare-Pandit, Albert C. Pierce, Suganthi Nanthakumar, Ron Grey, David Messersmith, James A. Henderson, Jon H. Come
Rok vydání:	2018
Předmět:	0301 basic medicine Encephalomyelitis Autoimmune Experimental Multiple Sclerosis Encephalomyelitis Drug Evaluation Preclinical Administration Oral Biological Availability Phthalimides Pharmacology Crystallography X-Ray Phosphatidylinositol 3-Kinases Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Adenosine Triphosphate 0302 clinical medicine Drug Discovery medicine Animals Humans Structure–activity relationship Enzyme Inhibitors Binding site Phosphoinositide-3 Kinase Inhibitors Binding Sites Phosphoinositide 3-kinase biology Chemistry Kinase Multiple sclerosis Experimental autoimmune encephalomyelitis Hydrogen Bonding medicine.disease Isoenzymes Mice Inbred C57BL 030104 developmental biology Drug Design 030220 oncology & carcinogenesis biology.protein Molecular Medicine Penetrant (biochemical)
Zdroj:	Journal of Medicinal Chemistry. 61:5245-5256
ISSN:	1520-4804 0022-2623
DOI:	10.1021/acs.jmedchem.8b00085
Popis:	The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5bd9109c79e1ecbf0788c161384fe50c https://doi.org/10.1021/acs.jmedchem.8b00085 Zobrazit plný text záznamu