3 research outputs found
Optimization of 1,2,4-Triazolopyridines as Inhibitors of Human 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD-1)
Small
alkyl groups and spirocyclic-aromatic rings directly attached
to the left side and right side of the 1,2,4-triazolopyridines (TZP),
respectively, were found to be potent and selective inhibitors of
human 11β-hydroxysteroid dehydrogenase-type 1 (11β-HSD-1)
enzyme. 3-(1-(4-Chlorophenyl)cyclopropyl)-8-cyclopropyl-[1,2,4]triazolo[4,3-<i>a</i>]pyridine (<b>9f</b>) was identified as a potent
inhibitor of the 11β-HSD-1 enzyme with reduced Pregnane-X receptor
(PXR) transactivation activity. The binding orientation of this TZP
series was revealed by X-ray crystallography structure studies
Discovery and Preclinical Evaluation of BMS-711939, an Oxybenzylglycine Based PPARα Selective Agonist
BMS-711939 (<b>3</b>) is a potent and selective peroxisome
proliferator-activated receptor (PPAR) α agonist, with an EC<sub>50</sub> of 4 nM for human PPARα and >1000-fold selectivity
vs human PPARγ (EC<sub>50</sub> = 4.5 μM) and PPARδ
(EC<sub>50</sub> > 100 μM) in PPAR-GAL4 transactivation assays.
Compound <b>3</b> also demonstrated excellent <i>in vivo</i> efficacy and safety profiles in preclinical studies and thus was
chosen for further preclinical evaluation. The synthesis, structure–activity
relationship (SAR) studies, and <i>in vivo</i> pharmacology
of <b>3</b> in preclinical animal models as well as its ADME
profile are described
Discovery of Clinical Candidate 2‑((2<i>S</i>,6<i>S</i>)‑2-Phenyl-6-hydroxyadamantan-2-yl)-1-(3′-hydroxyazetidin-1-yl)ethanone [BMS-816336], an Orally Active Novel Selective 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor
BMS-816336
(<b>6n-2</b>), a hydroxy-substituted adamantyl
acetamide, has been identified as a novel, potent inhibitor against
human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)
enzyme (IC<sub>50</sub> 3.0 nM) with >10000-fold selectivity over
human 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). <b>6n-2</b> exhibits a robust acute pharmacodynamic effect in cynomolgus
monkeys (ED<sub>50</sub> 0.12 mg/kg) and in DIO mice. It is orally
bioavailable (%<i>F</i> ranges from 20 to 72% in preclinical
species) and has a predicted pharmacokinetic profile of a high peak
to trough ratio and short half-life in humans. This ADME profile met
our selection criteria for once daily administration, targeting robust
inhibition of 11β-HSD1 enzyme for the first 12 h period after
dosing followed by an “inhibition holiday” so that the
potential for hypothalamic–pituitary–adrenal (HPA) axis
activation might be mitigated. <b>6n-2</b> was found to be well-tolerated
in phase 1 clinical studies and represents a potential new treatment
for type 2 diabetes, metabolic syndrome, and other human diseases
modulated by glucocorticoid control