2 research outputs found
2‑Aryl-3-methyloctahydrophenanthrene-2,3,7-triols as Potent Dissociated Glucocorticoid Receptor Agonists
A significant improvement in agonist
activity of the previously
described 2-aryloctahydrophenanthrene-2,3,7-triol series of dissociated
glucocorticoid receptor agonists (DAGRs) was achieved by modifying
the substitution at C3 from (<i>S</i>)-3-hydroxy to (<i>R</i>)-3-hydroxy-3-methyl. The IC<sub>50</sub> of the prototype <b>13</b> in the efficacy assay measuring repression of IL-1 induced
MMP-13 expression was 3.5 nM, exhibiting 87% of the maximal effect
of dexamethasone (DEX). It displayed a dissociated profile by exhibiting
42% of the maximal effect of DEX in a mouse mammary tumor virus (MMTV)
luciferase reporter transactivation assay. Compound <b>13</b> and analogues containing heterocyclic replacements for the C2 phenyl
and modified B rings showed high repression of TNFα production
in human whole blood, with IC<sub>50</sub> values (43–167 nM)
approaching the level of DEX (21 nM). On the basis of X-ray structures
and force field calculations, the overall potency of this series was
attributed to a favorable conformation of the C2α phenyl, induced
by the neighboring C3α methyl
Design, Synthesis, and Evaluation of Novel and Selective G‑protein Coupled Receptor 120 (GPR120) Spirocyclic Agonists
Type 2 diabetes mellitus
(T2DM) is an ever increasing worldwide
epidemic, and the identification of safe and effective insulin sensitizers,
absent of weight gain, has been a long-standing goal of diabetes research.
G-protein coupled receptor 120 (GPR120) has recently emerged as a
potential therapeutic target for treating T2DM. Natural occurring,
and more recently, synthetic agonists have been associated with insulin
sensitizing, anti-inflammatory, and fat metabolism effects. Herein
we describe the design, synthesis, and evaluation of a novel spirocyclic
GPR120 agonist series, which culminated in the discovery of potent
and selective agonist <b>14</b>. Furthermore, compound <b>14</b> was evaluated <i>in vivo</i> and demonstrated
acute glucose lowering in an oral glucose tolerance test (oGTT), as
well as improvements in homeostatic measurement assessment of insulin
resistance (HOMA-IR; a surrogate marker for insulin sensitization)
and an increase in glucose infusion rate (GIR) during a hyperinsulinemic
euglycemic clamp in diet-induced obese (DIO) mice