3 research outputs found
Urinary Globotriaosylsphingosine-Related Biomarkers for Fabry Disease Targeted by Metabolomics
Fabry disease is a lysosomal storage disorder caused
by deficiency
of Ī±-galactosidase A, resulting in glycosphingolipid accumulation
in organs and tissues, including plasma and urine. Two disease-specific
Fabry biomarkers have been identified and quantified in plasma and
urine: globotriaosylceramide (Gb<sub>3</sub>) and globotriaosylsphingosine
(lyso-Gb<sub>3</sub>). The search continues for biomarkers that might
be reliable indicators of disease severity and response to treatment.
The main objective of this study was to target other urinary biomarkers
using a time-of-flight mass spectrometry metabolomic approach. Urinary
metabolites of 63 untreated Fabry patients and 59 controls were analyzed.
A multivariate statistical analysis performed on a subset of male
samples revealed seven novel Fabry biomarkers in urine, all lyso-Gb<sub>3</sub> analogues having modified sphingosine moieties. The empirical
formulas of the sphingosine modifications were determined by exact
mass measurements (ā C<sub>2</sub>H<sub>4</sub>, ā C<sub>2</sub>H<sub>4</sub> + O, ā H<sub>2</sub>, ā H<sub>2</sub> + O, + O, + H<sub>2</sub>O<sub>2</sub>, + H<sub>2</sub>O<sub>3</sub>). We evaluated the relative concentration of lyso-Gb<sub>3</sub> and its seven analogues by measuring area counts for each
analogue in all Fabry patients. All samples were normalized to creatinine.
We found higher concentrations for males with Fabry disease compared
to females. None of these biomarkers were detected in controls. To
our knowledge, this is the first time that lyso-Gb<sub>3</sub>-related
Fabry disease biomarkers are detected in urine
Urinary Globotriaosylsphingosine-Related Biomarkers for Fabry Disease Targeted by Metabolomics
Fabry disease is a lysosomal storage disorder caused
by deficiency
of Ī±-galactosidase A, resulting in glycosphingolipid accumulation
in organs and tissues, including plasma and urine. Two disease-specific
Fabry biomarkers have been identified and quantified in plasma and
urine: globotriaosylceramide (Gb<sub>3</sub>) and globotriaosylsphingosine
(lyso-Gb<sub>3</sub>). The search continues for biomarkers that might
be reliable indicators of disease severity and response to treatment.
The main objective of this study was to target other urinary biomarkers
using a time-of-flight mass spectrometry metabolomic approach. Urinary
metabolites of 63 untreated Fabry patients and 59 controls were analyzed.
A multivariate statistical analysis performed on a subset of male
samples revealed seven novel Fabry biomarkers in urine, all lyso-Gb<sub>3</sub> analogues having modified sphingosine moieties. The empirical
formulas of the sphingosine modifications were determined by exact
mass measurements (ā C<sub>2</sub>H<sub>4</sub>, ā C<sub>2</sub>H<sub>4</sub> + O, ā H<sub>2</sub>, ā H<sub>2</sub> + O, + O, + H<sub>2</sub>O<sub>2</sub>, + H<sub>2</sub>O<sub>3</sub>). We evaluated the relative concentration of lyso-Gb<sub>3</sub> and its seven analogues by measuring area counts for each
analogue in all Fabry patients. All samples were normalized to creatinine.
We found higher concentrations for males with Fabry disease compared
to females. None of these biomarkers were detected in controls. To
our knowledge, this is the first time that lyso-Gb<sub>3</sub>-related
Fabry disease biomarkers are detected in urine
Optimization of the Potency and Pharmacokinetic Properties of a Macrocyclic Ghrelin Receptor Agonist (Part I): Development of Ulimorelin (TZP-101) from Hit to Clinic
High-throughput screening of Tranzyme Pharmaās
proprietary
macrocycle library using the aequorin Ca<sup>2+</sup>-bioluminescence
assay against the human ghrelin receptor (GRLN) led to the discovery
of novel agonists against this G-protein coupled receptor. Early hits
such as <b>1</b> (<i>K</i><sub>i</sub> = 86 nM, EC<sub>50</sub> = 134 nM) though potent in vitro displayed poor pharmacokinetic
properties that required optimization. While such macrocycles are
not fully rule-of-five compliant, principally due to their molecular
weight and clogP, optimization of their pharmacokinetic properties
proved feasible largely through conformational rigidification. Extensive
SAR led to the identification of <b>2</b> (<i>K</i><sub>i</sub> = 16 nM, EC<sub>50</sub> = 29 nM), also known as ulimorelin
or TZP-101, which has progressed to phase III human clinical trials
for the treatment of postoperative ileus. X-ray structure and detailed
NMR studies indicated a rigid peptidomimetic portion in <b>2</b> that is best defined as a nonideal type-Iā² Ī²-turn.
Compound <b>2</b> is 24% orally bioavailable in both rats and
monkeys. Despite its potency, in vitro and in gastric emptying studies, <b>2</b> did not induce growth hormone (GH) release in rats, thus
demarcating the GH versus GI pharmacology of GRLN