11 research outputs found
Synthesis of the Cortistatin Pentacyclic Core by Alkoxide-Directed Metallacycle-Mediated Annulative Cross-Coupling
The
pentacyclic core skeleton of the cortistatins has been prepared
in a stereoselective fashion by strategic use of an alkoxide-directed
metallacycle-mediated annulative cross-coupling. This metal-centered
tandem reaction delivers a polyunsaturated hydrindane and establishes
the C13 stereodefined quaternary center with high levels of stereocontrol.
Subsequent regio- and stereoselective global hydroboration results
in the realization of the DE-<i>trans</i> ring fusion and
a tertiary alcohol at C8. Establishment of the ABC-tricyclic subunit
was then accomplished through phenolic oxidation/<i>trans</i>-acetalization, chemoselective reduction, regioselective cleavage,
and intramolecular alkylation at C5
Enabling Asymmetric Synthesis of ABBV-3748, a Corrector Compound for the Treatment of Cystic Fibrosis
ABBV-3748
is a C2 corrector for the treatment of cystic fibrosis
profiled among AbbVieās CFTR portfolio. A decagram-scale enabling
asymmetric synthesis is described which addresses numerous shortcomings
of the original route. Highlights include an InBr3-catalyzed
intramolecular hydroarylation reaction that rapidly assembles the
chromane core, an exceptionally efficient asymmetric hydrogenation
of a primary enamide, and identification of tBuMgCl
as a uniquely effective base in a challenging acyl sulfonamide formation
Discovery of Small Molecule Interleukin 17A Inhibitors with Novel Binding Mode and Stoichiometry: Optimization of DNA-Encoded Chemical Library Hits to In Vivo Active Compounds
Dysregulation of IL17A drives numerous inflammatory and
autoimmune
disorders with inhibition of IL17A using antibodies proven as an effective
treatment. Oral anti-IL17 therapies are an attractive alternative
option, and several preclinical small molecule IL17 inhibitors have
previously been described. Herein, we report the discovery of a novel
class of small molecule IL17A inhibitors, identified via a DNA-encoded
chemical library screen, and their subsequent optimization to provide
in vivo efficacious inhibitors. These new proteināprotein interaction
(PPI) inhibitors bind in a previously undescribed mode in the IL17A
protein with two copies binding symmetrically to the central cavities
of the IL17A homodimer
Discovery of Small Molecule Interleukin 17A Inhibitors with Novel Binding Mode and Stoichiometry: Optimization of DNA-Encoded Chemical Library Hits to In Vivo Active Compounds
Dysregulation of IL17A drives numerous inflammatory and
autoimmune
disorders with inhibition of IL17A using antibodies proven as an effective
treatment. Oral anti-IL17 therapies are an attractive alternative
option, and several preclinical small molecule IL17 inhibitors have
previously been described. Herein, we report the discovery of a novel
class of small molecule IL17A inhibitors, identified via a DNA-encoded
chemical library screen, and their subsequent optimization to provide
in vivo efficacious inhibitors. These new proteināprotein interaction
(PPI) inhibitors bind in a previously undescribed mode in the IL17A
protein with two copies binding symmetrically to the central cavities
of the IL17A homodimer
Discovery of Small Molecule Interleukin 17A Inhibitors with Novel Binding Mode and Stoichiometry: Optimization of DNA-Encoded Chemical Library Hits to In Vivo Active Compounds
Dysregulation of IL17A drives numerous inflammatory and
autoimmune
disorders with inhibition of IL17A using antibodies proven as an effective
treatment. Oral anti-IL17 therapies are an attractive alternative
option, and several preclinical small molecule IL17 inhibitors have
previously been described. Herein, we report the discovery of a novel
class of small molecule IL17A inhibitors, identified via a DNA-encoded
chemical library screen, and their subsequent optimization to provide
in vivo efficacious inhibitors. These new proteināprotein interaction
(PPI) inhibitors bind in a previously undescribed mode in the IL17A
protein with two copies binding symmetrically to the central cavities
of the IL17A homodimer
Discovery of Small Molecule Interleukin 17A Inhibitors with Novel Binding Mode and Stoichiometry: Optimization of DNA-Encoded Chemical Library Hits to In Vivo Active Compounds
Dysregulation of IL17A drives numerous inflammatory and
autoimmune
disorders with inhibition of IL17A using antibodies proven as an effective
treatment. Oral anti-IL17 therapies are an attractive alternative
option, and several preclinical small molecule IL17 inhibitors have
previously been described. Herein, we report the discovery of a novel
class of small molecule IL17A inhibitors, identified via a DNA-encoded
chemical library screen, and their subsequent optimization to provide
in vivo efficacious inhibitors. These new proteināprotein interaction
(PPI) inhibitors bind in a previously undescribed mode in the IL17A
protein with two copies binding symmetrically to the central cavities
of the IL17A homodimer
Discovery of Small Molecule Interleukin 17A Inhibitors with Novel Binding Mode and Stoichiometry: Optimization of DNA-Encoded Chemical Library Hits to In Vivo Active Compounds
Dysregulation of IL17A drives numerous inflammatory and
autoimmune
disorders with inhibition of IL17A using antibodies proven as an effective
treatment. Oral anti-IL17 therapies are an attractive alternative
option, and several preclinical small molecule IL17 inhibitors have
previously been described. Herein, we report the discovery of a novel
class of small molecule IL17A inhibitors, identified via a DNA-encoded
chemical library screen, and their subsequent optimization to provide
in vivo efficacious inhibitors. These new proteināprotein interaction
(PPI) inhibitors bind in a previously undescribed mode in the IL17A
protein with two copies binding symmetrically to the central cavities
of the IL17A homodimer
Discovery of Small Molecule Interleukin 17A Inhibitors with Novel Binding Mode and Stoichiometry: Optimization of DNA-Encoded Chemical Library Hits to In Vivo Active Compounds
Dysregulation of IL17A drives numerous inflammatory and
autoimmune
disorders with inhibition of IL17A using antibodies proven as an effective
treatment. Oral anti-IL17 therapies are an attractive alternative
option, and several preclinical small molecule IL17 inhibitors have
previously been described. Herein, we report the discovery of a novel
class of small molecule IL17A inhibitors, identified via a DNA-encoded
chemical library screen, and their subsequent optimization to provide
in vivo efficacious inhibitors. These new proteināprotein interaction
(PPI) inhibitors bind in a previously undescribed mode in the IL17A
protein with two copies binding symmetrically to the central cavities
of the IL17A homodimer
Discovery of Small Molecule Interleukin 17A Inhibitors with Novel Binding Mode and Stoichiometry: Optimization of DNA-Encoded Chemical Library Hits to In Vivo Active Compounds
Dysregulation of IL17A drives numerous inflammatory and
autoimmune
disorders with inhibition of IL17A using antibodies proven as an effective
treatment. Oral anti-IL17 therapies are an attractive alternative
option, and several preclinical small molecule IL17 inhibitors have
previously been described. Herein, we report the discovery of a novel
class of small molecule IL17A inhibitors, identified via a DNA-encoded
chemical library screen, and their subsequent optimization to provide
in vivo efficacious inhibitors. These new proteināprotein interaction
(PPI) inhibitors bind in a previously undescribed mode in the IL17A
protein with two copies binding symmetrically to the central cavities
of the IL17A homodimer