Discovery of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent and selective PI3Kδ inhibitors

Autor:	Carolyn A. Weigelt, Xiaomei Gu, Stacey Skala, Paul Davies, Jenny Xie, John S. Sack, T. G. Murali Dhar, Melissa Yarde-Chinn, James Neels, Michael A. Poss, Stefan Ruepp, Robert J. Cherney, Christine Goldstein, Joseph A. Tino, Luisa Salter-Cid, Kevin Stefanski, Vojkan Susulic, Rajeev S. Bhide, Xiaoxia Yang, Anurag S. Srivastava, Zheming Ruan, Lan-Ying Qin, Cornelius Lyndon A M, Ruth Bosnius
Rok vydání:	2017
Předmět:	0301 basic medicine Class I Phosphatidylinositol 3-Kinases Stereochemistry Clinical Biochemistry Drug Evaluation Preclinical Pharmaceutical Science Pharmacology Crystallography X-Ray Biochemistry Piperazines Autoimmune Diseases Mice Phosphatidylinositol 3-Kinases Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Immune system In vivo Drug Discovery Animals Humans Protein Isoforms Amines Piperazine Protein Kinase Inhibitors Molecular Biology Phosphoinositide-3 Kinase Inhibitors Amine derivatives Binding Sites Triazines Organic Chemistry Alternative treatment Molecular Docking Simulation Disease Models Animal 030104 developmental biology chemistry 030220 oncology & carcinogenesis Microsomes Liver Molecular Medicine Lead compound
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 27:855-861
ISSN:	0960-894X
Popis:	As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and respiratory ailments. Herein, we disclose the identification of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse KLH model.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a62fd58c8612f99a2829596d8b0690e5 https://doi.org/10.1016/j.bmcl.2017.01.016 Zobrazit plný text záznamu Full Text from ScienceDirect