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
posted on 2018-05-31, 00:00authored byMichael Forster, Apirat Chaikuad, Teodor Dimitrov, Eva Döring, Julia Holstein, Benedict-Tilman Berger, Matthias Gehringer, Kamran Ghoreschi, Susanne Müller, Stefan Knapp, Stefan A. Laufer
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.