2 research outputs found
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
α‑Amino-β-carboxymuconate-ε-semialdehyde Decarboxylase (ACMSD) Inhibitors as Novel Modulators of De Novo Nicotinamide Adenine Dinucleotide (NAD<sup>+</sup>) Biosynthesis
NAD<sup>+</sup> has a central function in linking cellular metabolism
to major cell-signaling and gene-regulation pathways. Defects in NAD<sup>+</sup> homeostasis underpin a wide range of diseases, including
cancer, metabolic disorders, and aging. Although the beneficial effects
of boosting NAD<sup>+</sup> on mitochondrial fitness, metabolism,
and lifespan are well established, to date, no therapeutic enhancers
of de novo NAD<sup>+</sup> biosynthesis have been reported. Herein
we report the discovery of 3-[[[5-cyano-1,6-dihydro-6-oxo-4-(2-thienyl)-2-pyrimidinyl]thio]methyl]phenylacetic
acid (TES-1025, <b>22</b>), the first potent and selective inhibitor
of human ACMSD (IC<sub>50</sub> = 0.013 μM) that increases NAD<sup>+</sup> levels in cellular systems. The results of physicochemical-property,
ADME, and safety profiling, coupled with in vivo target-engagement
studies, support the hypothesis that ACMSD inhibition increases de
novo NAD<sup>+</sup> biosynthesis and position <b>22</b> as
a first-class molecule for the evaluation of the therapeutic potential
of ACMSD inhibition in treating disorders with perturbed NAD<sup>+</sup> supply or homeostasis