Design and Synthesis of Soluble and Cell-Permeable PI3Kδ Inhibitors for Long-Acting Inhaled Administration

Journal of Medicinal Chemistry
Matthew PerryLinda Öster

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 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.

References

Jan 1, 1995·Pharmaceutical Research·G HochhausT Dalla Costa
Mar 20, 1998·Journal of Clinical Pharmacology·G HochhausR J Gonzalez-Rothi
Feb 21, 2003·The Journal of Immunology : Official Journal of the American Association of Immunologists·Chanchal SadhuDonald E Staunton
Jul 11, 2003·Journal of Medicinal Chemistry·Rupert P AustinAlan Young
Dec 23, 2009·The Journal of Organic Chemistry·Christoffer Bengtsson, Fredrik Almqvist
Jan 1, 2009·Progress in Molecular Biology and Translational Science·Oded Meyuhas, Avigail Dreazen
Jul 5, 2011·Bioorganic & Medicinal Chemistry Letters·Stephen ConnollyAlan Young
Jan 21, 2012·Biochemical Society Transactions·Wendy C RowanAugustin Amour
Feb 4, 2012·Current Drug Metabolism·Anne E CooperKen Grime
Feb 18, 2012·Annual Review of Physiology·Joseph A Mindell
Mar 1, 2012·The Biochemical Journal·Lomon So, David A Fruman
Jun 8, 2012·Bioorganic & Medicinal Chemistry Letters·Daniel P SutherlinBinqing Wei
Aug 29, 2012·Journal of Medicinal Chemistry·Timothy D CushingLawrence R McGee
Apr 5, 2013·Annals of the New York Academy of Sciences·Srividya SriskantharajahAugustin Amour
Apr 5, 2013·Annals of the New York Academy of Sciences·Wai-Ping Fung-Leung
May 15, 2013·Chemical Science·Nicholas C BrunoStephen L Buchwald
Feb 1, 2014·Nature Reviews. Drug Discovery·David A Fruman, Christian Rommel
Sep 5, 2014·Drugs·Anthony Markham
Dec 17, 2014·Biochimica Et Biophysica Acta·P T Hawkins, L R Stephens
Mar 3, 2015·Leukemia & Lymphoma·Steven E CoutréAndrew D Zelenetz
Jun 29, 2015·Current Opinion in Pharmacology·Timothy A YapPaul Workman
Dec 15, 2015·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Bart VanhaesebroeckRoberto Piñeiro
Jan 19, 2016·Global Cardiology Science & Practice·Ibrahim M El-SherbinyMagdi H Yacoub
Sep 28, 2016·Journal of Pharmaceutical Sciences·Erica BäckströmMarkus Fridén
Dec 27, 2016·Bioorganic & Medicinal Chemistry Letters·Ina TerstiegeLinda Öster

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Citations

Jul 27, 2018·Journal of Biomolecular Structure & Dynamics·Shubham SrivastavaRuchi Malik
Mar 1, 2019·Biomolecules·Michelle S MillerSandra B Gabelli
Apr 20, 2019·Medicinal Research Reviews·Xiangyi JiangPeng Zhan
Apr 3, 2021·Journal of Medicinal Chemistry·Joey L MethotJason D Katz
Jun 4, 2021·Journal of Medicinal Chemistry·Matthew W D PerryLinda Öster
Apr 16, 2019·Journal of Medicinal Chemistry·Joey L MethotJason D Katz
Dec 26, 2018·Journal of Medicinal Chemistry·Aimie E Garces, Michael J Stocks
Dec 26, 2018·Journal of Medicinal Chemistry·Matthew W D PerryAnnika Westin Eriksson

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