Development, Optimization, and Structure-Activity Relationships of Covalent-Reversible JAK3 Inhibitors Based on a Tricyclic Imidazo[5,4- d]pyrrolo[2,3- b]pyridine Scaffold

Journal of Medicinal Chemistry
Michael ForsterStefan A Laufer

Abstract

Janus kinases are major drivers of immune signaling and have been the focus of anti-inflammatory drug discovery for more than a decade. Because of the invariable colocalization of JAK1 and JAK3 at cytokine receptors, the question if selective JAK3 inhibition is sufficient to effectively block downstream signaling has been highly controversial. Recently, we discovered the covalent-reversible JAK3 inhibitor FM-381 (23) featuring high isoform and kinome selectivity. Crystallography revealed that this inhibitor induces an unprecedented binding pocket by interactions of a nitrile substituent with arginine residues in JAK3. Herein, we describe detailed structure-activity relationships necessary for induction of the arginine pocket and the impact of this structural change on potency, isoform selectivity, and efficacy in cellular models. Furthermore, we evaluated the stability of this novel inhibitor class in in vitro metabolic assays and were able to demonstrate an adequate stability of key compound 23 for in vivo use.

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Citations

Dec 7, 2018·Future Medicinal Chemistry·Yuanxun WangNiu Huang
Nov 20, 2019·Der Hautarzt; Zeitschrift für Dermatologie, Venerologie, und verwandte Gebiete·F SolimaniK Ghoreschi
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Dec 10, 2020·International Journal of Molecular Sciences·Michael ForsterMatthias Gehringer
May 14, 2021·Scientific Reports·Judit RemenyiJ Simon C Arthur
May 18, 2021·Journal of Chemical Information and Modeling·Maria Galvez-LlompartMaurizio Recanatini
Feb 15, 2019·Journal of Chemical Information and Modeling·Han ZhangYun Luo
Sep 4, 2021·Journal of Medicinal Chemistry·Ricardo A M SerafimMatthias Gehringer
Sep 29, 2021·Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG·Kamran GhoreschiDiamant Thaçi
Dec 29, 2021·Journal of Medicinal Chemistry·Xiaoyun LuKe Ding

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