2 research outputs found
Discovery of Diarylhydantoins as New Selective Androgen Receptor Modulators
A novel selective androgen receptor modulator scaffold
has been
discovered through structural modifications of hydantoin antiandrogens.
Several 4-(4-hydroxyphenyl)-<i>N</i>-arylhydantoins displayed
partial agonism with nanomolar in vitro potency in transactivation
experiments using androgen receptor (AR) transfected cells. In a standard
castrated male rat model, several compounds showed good anabolic activity
on levator ani muscle, dissociated from the androgenic activity on
ventral prostate, after oral dosing at 30 mg/kg. (+)-4-[3,4-Dimethyl-2,5-dioxo-4-(4-hydroxyphenyl)imidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile
((+)-<b>11b</b>) displayed anabolic potency with a strong dissociation
between levator ani muscle and ventral prostate (<i>A</i><sub>50</sub> = 0.5 mg/kg vs 70 mg/kg). The binding modes of two
compounds, including (+)-<b>11b</b>, within the AR ligand-binding
domain have been studied by cocrystallization experiments using a
coactivator-like peptide. Both compounds bound to the same site, and
the overall structures of the AR were very similar
Discovery, Structure–Activity Relationship, and Binding Mode of an Imidazo[1,2‑<i>a</i>]pyridine Series of Autotaxin Inhibitors
Autotaxin
(ATX) is a secreted enzyme playing a major role in the
production of lysophosphatidic acid (LPA) in blood through hydrolysis
of lysophosphatidyl choline (LPC). The ATX–LPA signaling axis
arouses a high interest in the drug discovery industry as it has been
implicated in several diseases including cancer, fibrotic diseases,
and inflammation, among others. An imidazo[1,2-<i>a</i>]pyridine
series of ATX inhibitors was identified out of a high-throughput screening
(HTS). A cocrystal structure with one of these compounds and ATX revealed
a novel binding mode with occupancy of the hydrophobic pocket and
channel of ATX but no interaction with zinc ions of the catalytic
site. Exploration of the structure–activity relationship led
to compounds displaying high activity in biochemical and plasma assays,
exemplified by compound <b>40</b>. Compound <b>40</b> was
also able to decrease the plasma LPA levels upon oral administration
to rats