2 research outputs found
Building a Sulfonamide Library by Eco-Friendly Flow Synthesis
A rapid and eco-friendly synthesis
of a sulfonamide library under
flow conditions is described. The study illustrates an efficient,
safe, and easily scalable preparation of sulfonamides by use of a
meso-reactor apparatus, thus demonstrating the impact of flow technologies
within drug discovery. Waste minimization, employment of green media,
and nontoxic reactants are achieved by the optimization of the flow
setup and experimental protocol designed to sequentially synthesize
primary, secondary, and tertiary sulfonamides. Isolation of the products
involves only extraction and precipitation affording pure compounds
in good to high yields without further purification for biological
evaluation
Discovery of 3α,7α,11β-Trihydroxy-6α-ethyl-5β-cholan-24-oic Acid (TC-100), a Novel Bile Acid as Potent and Highly Selective FXR Agonist for Enterohepatic Disorders
As a continuation of previous efforts
in mapping functional hot
spots on the bile acid scaffold, we here demonstrate that the introduction
of a hydroxy group at the C11β position affords high selectivity
for FXR. In particular, the synthesis and FXR/TGR5 activity of novel
bile acids bearing different hydroxylation patterns at the C ring
are reported and discussed from a structure–activity standpoint.
The results obtained led us to discover the first bile acid derivative
endowed with high potency and selectivity at the FXR receptor, 3α,7α,11β-trihydroxy-6α-ethyl-5β-cholan-24-oic
acid (TC-100, <b>7</b>) which also shows a remarkable physicochemical
and pharmacological profile. Compound <b>7</b> combines the
excellent physicochemical properties of hydrophilic bile acids such
as ursodeoxycholic acid, with the distinct ability to specifically
bind and regulate FXR activity in vivo, thus providing a bona fide novel therapeutic agent to treat enterohepatic
disorders such as cholestasis, NASH, and inflammatory bowel disease