4 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)Âcyclopropyl)-8-cyclopropyl-[1,2,4]ÂtriazoloÂ[4,3-<i>a</i>]Âpyridine (<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 of 5‑Chloro-4-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1<i>H</i>)‑one (BMS-903452), an Antidiabetic Clinical Candidate Targeting GPR119
G-protein-coupled receptor 119 (GPR119)
is expressed predominantly in pancreatic β-cells and in enteroendocrine
cells in the gastrointestinal tract. GPR119 agonists have been shown
to stimulate glucose-dependent insulin release by direct action in
the pancreas and to promote secretion of the incretin GLP-1 by action
in the gastrointestinal tract. This dual mechanism of action has generated
significant interest in the discovery of small molecule GPR119 agonists
as a potential new treatment for type 2 diabetes. Herein, we describe
the discovery and optimization of a new class of pyridone containing
GPR119 agonists. The potent and selective BMS-903452 (<b>42</b>) was efficacious in both acute and chronic in vivo rodent models
of diabetes. Dosing of <b>42</b> in a single ascending dose
study in normal healthy humans showed a dose dependent increase in
exposure and a trend toward increased total GLP-1 plasma levels
Discovery of Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists
G protein-coupled
receptor 40 (GPR40) has become an attractive
target for the treatment of diabetes since it was shown clinically
to promote glucose-stimulated insulin secretion. Herein, we report
our efforts to develop highly selective and potent GPR40 agonists
with a dual mechanism of action, promoting both glucose-dependent
insulin and incretin secretion. Employing strategies to increase polarity
and the ratio of sp<sup>3</sup>/sp<sup>2</sup> character of the chemotype,
we identified BMS-986118 (compound <b>4</b>), which showed potent
and selective GPR40 agonist activity <i>in vitro</i>. <i>In vivo</i>, compound <b>4</b> demonstrated insulinotropic
efficacy and GLP-1 secretory effects resulting in improved glucose
control in acute animal models
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