Design and synthesis of soluble and cell-permeable PI3Kδ inhibitors for long-acting inhaled administration

Perry, Matthew W. D. and Björhall, Karin and Bonn, Britta K. and Carlsson, Johan and Chen, Yunhua and Eriksson, Anders and Fredlund, Linda and Hao, Hai'e and Holden, Neil S. and Karabelas, Kostas and Lindmark, Helena and Liu, Feifei and Pemberton, Nils and Petersen, Jens and Rodrigo Blomqvist, Sandra and Smith, Reed W. and Svensson, Tor and Terstiege, Ina and Tyrchan, Christian and Yang, Wenzhen and Zhao, Shuchun and Öster, Linda (2017) Design and synthesis of soluble and cell-permeable PI3Kδ inhibitors for long-acting inhaled administration. Journal of Medicinal Chemistry . ISSN 0022-2623

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Abstract

PI3Kδ is a lipid kinase that is believed to be important in the migration and activation of cells of the immune system. Inhibition is hypothesised 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 optimisation 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.

Keywords:bmjconvert
Subjects:B Subjects allied to Medicine > B100 Anatomy, Physiology and Pathology
B Subjects allied to Medicine > B200 Pharmacology, Toxicology and Pharmacy
Divisions:College of Science > School of Life Sciences
ID Code:27586
Deposited On:24 May 2017 13:28

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