4 research outputs found
New avenues in nitrenium ion and carbenen chemistry: Total synthesis of TAN1251A, cinatrin B, C(1), and C(3).
New avenues in nitrenium ion and carbenen chemistry: Total synthesis of TAN1251A, cinatrin B, C(1), and C(3)
Intrinsic Electrophilicity of a 4-Substituted-5-cyano-6-(2-methylpyridin-3-yloxy)pyrimidine Derivative: Structural Characterization of Glutathione Conjugates in Vitro
Structure-Based Design of Highly Selective Inhibitors of the CREB Binding Protein Bromodomain
Chemical
probes are required for preclinical target validation
to interrogate novel biological targets and pathways. Selective inhibitors
of the CREB binding protein (CREBBP)/EP300 bromodomains are required
to facilitate the elucidation of biology associated with these important
epigenetic targets. Medicinal chemistry optimization that paid particular
attention to physiochemical properties delivered chemical probes with
desirable potency, selectivity, and permeability attributes. An important
feature of the optimization process was the successful application
of rational structure-based drug design to address bromodomain selectivity
issues (particularly against the structurally related BRD4 protein)
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