4 research outputs found
Investigating Nephrotoxicity of Polymyxin Derivatives by Mapping Renal Distribution Using Mass Spectrometry Imaging
Colistin
and polymyxin B are effective treatment options for Gram-negative
resistant bacteria but are used as last-line therapy due to their
dose-limiting nephrotoxicity. A critical factor in developing safer
polymyxin analogues is understanding accumulation of the drugs and
their metabolites, which is currently limited due to the lack of effective
techniques for analysis of these challenging molecules. Mass spectrometry
imaging (MSI) allows direct detection of targets (drugs, metabolites,
and endogenous compounds) from tissue sections. The presented study
exemplifies the utility of MSI by measuring the distribution of polymyxin
B1, colistin, and polymyxin B nonapeptide (PMBN) within dosed rat
kidney tissue sections. The label-free MSI analysis revealed that
the nephrotoxic compounds (polymyxin B1 and colistin) preferentially
accumulated in the renal cortical region. The less nephrotoxic analogue,
polymyxin B nonapeptide, was more uniformly distributed throughout
the kidney. In addition, metabolites of the dosed compounds were detected
by MSI. Kidney homogenates were analyzed using LC/MS/MS to determine
total drug exposure and for metabolite identification. To our knowledge,
this is the first time such techniques have been utilized to measure
the distribution of polymyxin drugs and their metabolites. By simultaneously
detecting the distribution of drug and drug metabolites, MSI offers
a powerful alternative to tissue homogenization analysis and label
or antibody-based imaging
Optimization of Brain Penetrant 11β-Hydroxysteroid Dehydrogenase Type I Inhibitors and in Vivo Testing in Diet-Induced Obese Mice
11β-Hydroxysteroid
dehydrogenase type 1 (11β-HSD1)
has been widely considered by the pharmaceutical industry as a target
to treat metabolic syndrome in type II diabetics. We hypothesized
that central nervous system (CNS) penetration might be required to
see efficacy. Starting from a previously reported pyrimidine compound,
we removed hydrogen-bond donors to yield <b>3</b>, which had
modest CNS penetration. More significant progress was achieved by
changing the core to give <b>40</b>, which combines good potency
and CNS penetration. Compound <b>40</b> was dosed to diet-induced
obese (DIO) mice and gave excellent target engagement in the liver
and high free exposures of drug, both peripherally and in the CNS.
However, no body weight reduction or effects on glucose or insulin
were observed in this model. Similar data were obtained with a structurally
diverse thiazole compound <b>51</b>. This work casts doubt on
the hypothesis that localized tissue modulation of 11β-HSD1
activity alleviates metabolic syndrome
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