jm7b00401_si_001.pdf (2.51 MB)
Design and Synthesis of Soluble and Cell-Permeable PI3Kδ Inhibitors for Long-Acting Inhaled Administration
journal contribution
posted on 2017-05-18, 00:00 authored by Matthew W. D. Perry, Karin Björhall, Britta Bonn, Johan Carlsson, Yunhua Chen, Anders Eriksson, Linda Fredlund, Hai’e Hao, Neil S. Holden, Kostas Karabelas, Helena Lindmark, Feifei Liu, Nils Pemberton, Jens Petersen, Sandra Rodrigo Blomqvist, Reed W. Smith, Tor Svensson, Ina Terstiege, Christian Tyrchan, Wenzhen Yang, Shuchun Zhao, Linda ÖsterPI3Kδ
is a lipid kinase that is believed to be important
in the migration and activation of cells of the immune system. Inhibition
is hypothesized to provide a powerful yet selective immunomodulatory
effect that may be beneficial for the treatment of conditions such
as asthma or rheumatoid arthritis. In this work, we describe the identification
of inhibitors based on a thiazolopyridone core structure and their
subsequent optimization for inhalation. The initially identified compound
(13) had good potency and isoform selectivity but was
not suitable for inhalation. Addition of basic substituents to a region
of the molecule pointing to solvent was tolerated (enzyme inhibition
pIC50 > 9), and by careful manipulation of the pKa and lipophilicity, we were able to discover
compounds (20b, 20f) with good lung retention
and cell potency that could be taken forward to in vivo studies where
significant target engagement could be demonstrated.
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lipid kinasemanipulationmigrationp Kvivo studiessubstituentcell potencyasthmalung retentionInhibitionidentificationLong-Acting Inhaled Administration PI 3KSynthesi20 benzyme inhibition pIC 50activationarthritismoleculeCell-Permeable PI 3K Inhibitorslipophilicitycompoundisoform selectivityinhalationimmunomodulatory effectregiontarget engagementSolubleoptimizationthiazolopyridone core structure20 finhibitor
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