Discovery and SAR of pyrrolo[2,1-f][1,2,4]triazin-4-amines as potent and selective PI3Kδ inhibitors

[Display omitted] Aberrant Class I PI3K signaling is a key factor contributing to many immunological disorders and cancers. We have identified 4-amino pyrrolotriazine as a novel chemotype that selectively inhibits PI3Kδ signaling despite not binding to the specificity pocket of PI3Kδ isoform. Struct...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2016-09, Vol.26 (17), p.4256-4260
Hauptverfasser:	Bhide, Rajeev S., Neels, James, Qin, Lan-Ying, Ruan, Zheming, Stachura, Sylwia, Weigelt, Carolyn, Sack, John S., Stefanski, Kevin, Gu, Xiaomei, Xie, Jenny H., Goldstine, Christine B., Skala, Stacey, Pedicord, Donna L., Ruepp, Stefan, Dhar, T.G. Murali, Carter, Percy H., Salter-Cid, Luisa M., Poss, Michael A., Davies, Paul
Format:	Artikel
Sprache:	eng
Schlagworte:	Amines - chemistry Amines - metabolism Amines - therapeutic use Animals Arthritis - drug therapy Arthritis - metabolism Arthritis - pathology Binding Sites Disease Models, Animal Drug Evaluation, Preclinical Inhibitory Concentration 50 Mice Molecular Docking Simulation Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - metabolism Phosphatidylinositol-3 kinases PI3Kδ Protein Binding Protein Isoforms - antagonists & inhibitors Protein Isoforms - metabolism Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - metabolism Protein Kinase Inhibitors - therapeutic use Protein Structure, Tertiary Pyrrolo[2,1-f][1,2,4]triazin-4-amine Rheumatoid arthritis Structure-Activity Relationship Triazines - chemistry
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Zusammenfassung:	[Display omitted] Aberrant Class I PI3K signaling is a key factor contributing to many immunological disorders and cancers. We have identified 4-amino pyrrolotriazine as a novel chemotype that selectively inhibits PI3Kδ signaling despite not binding to the specificity pocket of PI3Kδ isoform. Structure activity relationship (SAR) led to the identification of compound 30 that demonstrated efficacy in mouse Keyhole Limpet Hemocyanin (KLH) and collagen induced arthritis (CIA) models.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2016.07.047