2 research outputs found
Novel Acidic 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitor with Reduced Acyl Glucuronide Liability: The Discovery of 4‑[4-(2-Adamantylcarbamoyl)-5-<i>tert</i>-butyl-pyrazol-1-yl]benzoic Acid (AZD8329)
Inhibition of 11β-HSD1 is viewed as a potential
target for
the treatment of obesity and other elements of the metabolic syndrome.
We report here the optimization of a carboxylic acid class of inhibitors
from AZD4017 (<b>1</b>) to the development candidate AZD8329
(<b>27</b>). A structural change from pyridine to pyrazole together
with structural optimization led to an improved technical profile
in terms of both solubility and pharmacokinetics. The extent of acyl
glucuronidation was reduced through structural optimization of both
the carboxylic acid and amide substituents, coupled with a reduction
in lipophilicity leading to an overall increase in metabolic stability
Discovery of a Potent, Selective, and Orally Bioavailable Acidic 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitor: Discovery of 2-[(3<i>S</i>)-1-[5-(Cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]-3-piperidyl]acetic Acid (AZD4017)
Inhibition of 11β-HSD1 is an attractive mechanism
for the
treatment of obesity and other elements of the metabolic syndrome.
We report here the discovery of a nicotinic amide derived carboxylic
acid class of inhibitors that has good potency, selectivity, and pharmacokinetic
characteristics. Compound <b>11i</b> (AZD4017) is an effective
inhibitor of 11β-HSD1 in human adipocytes and exhibits good
druglike properties and as a consequence was selected for clinical
development