Discovery and in vivo evaluation of (S)-N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and related PI3Kδ inhibitors for inflammation and autoimmune disease

  • J Med Chem. 2015 Jan 8;58(1):480-511. doi: 10.1021/jm501624r.
Timothy D Cushing  1 ,  Xiaolin Hao ,  Youngsook Shin ,  Kristin Andrews ,  Matthew Brown ,  Mario Cardozo ,  Yi Chen ,  Jason Duquette ,  Ben Fisher ,  Felix Gonzalez-Lopez de Turiso ,  Xiao He ,  Kirk R Henne ,  Yi-Ling Hu ,  Randall Hungate ,  Michael G Johnson ,  Ron C Kelly ,  Brian Lucas ,  John D McCarter ,  Lawrence R McGee ,  Julio C Medina ,  Tisha San Miguel ,  Deanna Mohn ,  Vatee Pattaropong ,  Liping H Pettus ,  Andreas Reichelt ,  Robert M Rzasa ,  Jennifer Seganish ,  Andrew S Tasker ,  Robert C Wahl ,  Sharon Wannberg ,  Douglas A Whittington ,  John Whoriskey ,  Gang Yu ,  Leeanne Zalameda ,  Dawei Zhang ,  Daniela P Metz
Affiliations
  • 1. Department of Therapeutic Discovery, ‡Department of Pharmacokinetics and Drug Metabolism, and §Department of Pharmaceutics Research and Development, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
PMID: 25469863 DOI: 10.1021/jm501624r
Abstract

The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12948
    AMG319
    99.09%, PI3Kδ Inhibitor
    target: PI3K
    Research Areas: Cancer