4 research outputs found
Synthesis of Fused Imidazole-Containing Ring Systems via Dual Oxidative Amination of C(sp<sup>3</sup>)–H Bonds
A general and efficient
method for a metal-free one-pot synthesis
of highly substituted fused imidazole-containing 5,5- and 5,6-fused
bicyclic heterocycles is described. Starting from commercially available
substrates and reagents, the reaction proceeds through two C–N
bond formations and an oxidative dehydrogenation to form highly substituted
products in good to excellent yield
Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton’s Tyrosine Kinase Inhibitor in Early Clinical Development
Bruton’s
tyrosine kinase (Btk) is a nonreceptor cytoplasmic
tyrosine kinase involved in B-cell and myeloid cell activation, downstream
of B-cell and Fcγ receptors, respectively. Preclinical studies
have indicated that inhibition of Btk activity might offer a potential
therapy in autoimmune diseases such as rheumatoid arthritis and systemic
lupus erythematosus. Here we disclose the discovery and preclinical
characterization of a potent, selective, and noncovalent Btk inhibitor
currently in clinical development. GDC-0853 (<b>29</b>) suppresses
B cell- and myeloid cell-mediated components of disease and demonstrates
dose-dependent activity in an <i>in vivo</i> rat model of
inflammatory arthritis. It demonstrates highly favorable safety, pharmacokinetic
(PK), and pharmacodynamic (PD) profiles in preclinical and Phase 2
studies ongoing in patients with rheumatoid arthritis, lupus, and
chronic spontaneous urticaria. On the basis of its potency, selectivity,
long target residence time, and noncovalent mode of inhibition, <b>29</b> has the potential to be a best-in-class Btk inhibitor for
a wide range of immunological indications
Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton’s Tyrosine Kinase Inhibitor in Early Clinical Development
Bruton’s
tyrosine kinase (Btk) is a nonreceptor cytoplasmic
tyrosine kinase involved in B-cell and myeloid cell activation, downstream
of B-cell and Fcγ receptors, respectively. Preclinical studies
have indicated that inhibition of Btk activity might offer a potential
therapy in autoimmune diseases such as rheumatoid arthritis and systemic
lupus erythematosus. Here we disclose the discovery and preclinical
characterization of a potent, selective, and noncovalent Btk inhibitor
currently in clinical development. GDC-0853 (<b>29</b>) suppresses
B cell- and myeloid cell-mediated components of disease and demonstrates
dose-dependent activity in an <i>in vivo</i> rat model of
inflammatory arthritis. It demonstrates highly favorable safety, pharmacokinetic
(PK), and pharmacodynamic (PD) profiles in preclinical and Phase 2
studies ongoing in patients with rheumatoid arthritis, lupus, and
chronic spontaneous urticaria. On the basis of its potency, selectivity,
long target residence time, and noncovalent mode of inhibition, <b>29</b> has the potential to be a best-in-class Btk inhibitor for
a wide range of immunological indications
Discovery of Novel PI3-Kinase δ Specific Inhibitors for the Treatment of Rheumatoid Arthritis: Taming CYP3A4 Time-Dependent Inhibition
PI3Kδ is a lipid kinase and a member of a larger
family of enzymes, PI3K class IAÂ(α, β, δ) and IB
(γ), which catalyze the phosphorylation of PIP2 to PIP3. PI3Kδ
is mainly expressed in leukocytes, where it plays a critical, nonredundant
role in B cell receptor mediated signaling and provides an attractive
opportunity to treat diseases where B cell activity is essential,
e.g., rheumatoid arthritis. We report the discovery of novel, potent,
and selective PI3Kδ inhibitors and describe a structural hypothesis
for isoform (α, β, γ) selectivity gained from interactions
in the affinity pocket. The critical component of our initial pharmacophore
for isoform selectivity was strongly associated with CYP3A4 time-dependent
inhibition (TDI). We describe a variety of strategies and methods
for monitoring and attenuating TDI. Ultimately, a structure-based
design approach was employed to identify a suitable structural replacement
for further optimization