2 research outputs found
Identification of <i>N</i>‑{<i>cis</i>-3-[Methyl(7<i>H</i>‑pyrrolo[2,3‑<i>d</i>]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases
Janus kinases (JAKs)
are intracellular tyrosine kinases that mediate
the signaling of numerous cytokines and growth factors involved in
the regulation of immunity, inflammation, and hematopoiesis. As JAK1
pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would
be expected to inhibit many cytokines involved in inflammation and
immune function while avoiding inhibition of the JAK2 homodimer regulating
erythropoietin and thrombopoietin signaling. Our efforts began with
tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid
arthritis. Through modification of the 3-aminopiperidine linker in
tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar
potency in a human whole blood assay. Improvements in JAK1 potency
and selectivity were achieved via structural modifications suggested
by X-ray crystallographic analysis. After demonstrating efficacy in
a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (<b>25</b>) was nominated as a clinical candidate for the treatment
of JAK1-mediated autoimmune diseases
Discovery of Clinical Candidate 1‑{[(2<i>S</i>,3<i>S</i>,4<i>S</i>)‑3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin‑1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design
Through
fragment-based drug design focused on engaging the active
site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient
manner, a micromolar hit identified from a screen of a Pfizer fragment
library was optimized to afford IRAK4 inhibitors with nanomolar potency
in cellular assays. The medicinal chemistry effort featured the judicious
placement of lipophilicity, informed by co-crystal structures with
IRAK4 and optimization of ADME properties to deliver clinical candidate
PF-06650833 (compound <b>40</b>). This compound displays a 5-unit
increase in lipophilic efficiency from the fragment hit, excellent
kinase selectivity, and pharmacokinetic properties suitable for oral
administration