38 research outputs found
Asymmetric Synthesis of a Glucagon Receptor Antagonist via Friedel–Crafts Alkylation of Indole with Chiral α‑Phenyl Benzyl Cation
Development of a practical asymmetric synthesis of a
glucagon receptor
antagonist drug candidate for the treatment of type 2 diabetes is
described. The antagonist consists of a 1,1,2,2-tetrasubstituted ethane
core substituted with a propyl and three aryl groups including a fluoro-indole.
The key steps to construct the ethane core and the two stereogenic
centers involved a ketone arylation, an asymmetric hydrogenation via
dynamic kinetic resolution, and an <i>anti</i>-selective
Friedel–Crafts alkylation of a fluoro-indole with a chiral
α-phenyl benzyl cation. We also developed two new efficient
syntheses of the fluoro-indole, including an unusual Larock-type indole
synthesis and a Sugasawa-heteroannulation route. The described convergent
synthesis was used to prepare drug substance in 52% overall yield
and 99% ee on multikilogram scales
Discovery of 5‑Amino‑<i>N</i>‑(1<i>H</i>‑pyrazol-4-yl)pyrazolo[1,5‑<i>a</i>]pyrimidine-3-carboxamide Inhibitors of IRAK4
Interleukin-1
receptor associated kinase 4 (IRAK4) is an essential
signal transducer downstream of the IL-1R and TLR superfamily, and
selective inhibition of the kinase activity of the protein represents
an attractive target for the treatment of inflammatory diseases. A
series of 5-amino-<i>N</i>-(1<i>H</i>-pyrazol-4-yl)pyrazolo[1,5-<i>a</i>]pyrimidine-3-carboxamides was developed via sequential
modifications to the 5-position of the pyrazolopyrimidine ring and
the 3-position of the pyrazole ring. Replacement of substituents responsible
for poor permeability and improvement of physical properties guided
by cLogD led to the identification of IRAK4 inhibitors with excellent
potency, kinase selectivity, and pharmacokinetic properties suitable
for oral dosing
Asymmetric Synthesis of a Glucagon Receptor Antagonist via Friedel–Crafts Alkylation of Indole with Chiral α‑Phenyl Benzyl Cation
Development of a practical asymmetric synthesis of a
glucagon receptor
antagonist drug candidate for the treatment of type 2 diabetes is
described. The antagonist consists of a 1,1,2,2-tetrasubstituted ethane
core substituted with a propyl and three aryl groups including a fluoro-indole.
The key steps to construct the ethane core and the two stereogenic
centers involved a ketone arylation, an asymmetric hydrogenation via
dynamic kinetic resolution, and an <i>anti</i>-selective
Friedel–Crafts alkylation of a fluoro-indole with a chiral
α-phenyl benzyl cation. We also developed two new efficient
syntheses of the fluoro-indole, including an unusual Larock-type indole
synthesis and a Sugasawa-heteroannulation route. The described convergent
synthesis was used to prepare drug substance in 52% overall yield
and 99% ee on multikilogram scales