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2.
Bioorg Med Chem Lett ; 26(23): 5724-5728, 2016 12 01.
Article in English | MEDLINE | ID: mdl-27815121

ABSTRACT

The transformation of an aryloxybutanoic acid ultra high-throughput screening (uHTS) hit into a potent and selective series of G-protein coupled receptor 120 (GPR120) agonists is reported. uHTS hit 1 demonstrated an excellent rodent pharmacokinetic profile and selectivity over the related fatty acid receptor GPR40, but only modest GPR120 potency. Optimization of the "left-hand" aryl group led to compound 6, which demonstrated a GPR120 mechanism-based pharmacodynamic effect in a mouse oral glucose tolerance test (oGTT). Further optimization gave rise to the benzofuran propanoic acid series (exemplified by compound 37), which demonstrated acute mechanism-based pharmacodynamic effects. The combination of in vivo efficacy and attractive rodent pharmacodynamic profiles suggests compounds generated from this series may afford attractive candidates for the treatment of Type 2 diabetes.


Subject(s)
Benzofurans/chemistry , Benzofurans/pharmacology , Propionates/chemistry , Propionates/pharmacology , Receptors, G-Protein-Coupled/agonists , Animals , Benzofurans/blood , Blood Glucose/analysis , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Drug Evaluation, Preclinical , High-Throughput Screening Assays , Humans , Hypoglycemic Agents/blood , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Mice , Propionates/blood , Receptors, G-Protein-Coupled/metabolism
3.
Bioanalysis ; 5(3): 275-9, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23394693

ABSTRACT

This annual meeting began in 1998 and was the first industry-led event to focus on the specific needs of industry researchers. The goal of Clinical and Pharmaceutical Solutions Through Analysis (CPSA) is to provide an in-depth review of innovative technology and industry practices through open discussion of industry-related issues and needs. Education and specialized training are the foundation of all CPSA events. As the industry has evolved so has CPSA. Thus, the year the name was changed from Chemical and Pharmaceutical Structural Analysis to CPSA was to reflect the growing focus on clinical applications and the emergence of personalized medicine. Most importantly, the CPSA annual meeting has retained the same high-quality scientific content, open interaction from industry opinion leaders and a collegial environment.


Subject(s)
Drug Discovery/methods , Drug Discovery/trends , Humans , Research Design
4.
Toxicol Appl Pharmacol ; 255(1): 48-56, 2011 Aug 15.
Article in English | MEDLINE | ID: mdl-21640743

ABSTRACT

An investigative renal toxicity study using metabolomics was conducted with a potent nicotinic acid receptor (NAR) agonist, SCH 900424. Liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) techniques were used to identify small molecule biomarkers of acute kidney injury (AKI) that could aid in a better mechanistic understanding of SCH 900424-induced AKI in mice. The metabolomics study revealed 3-indoxyl sulfate (3IS) as a more sensitive marker of SCH 900424-induced renal toxicity than creatinine or urea. An LC-MS assay for quantitative determination of 3IS in mouse matrices was also developed. Following treatment with SCH 900424, 3IS levels were markedly increased in murine plasma and brain, thereby potentially contributing to renal- and central nervous system (CNS)-related rapid onset of toxicities. Furthermore, significant decrease in urinary excretion of 3IS in those animals due to compromised renal function may be associated with the elevation of 3IS in plasma and brain. These data suggest that 3IS has a potential to be a marker of renal and CNS toxicities during chemically-induced AKI in mice. In addition, based on the metabolomic analysis other statistically significant plasma markers including p-cresol-sulfate and tryptophan catabolites (kynurenate, kynurenine, 3-indole-lactate) might be of toxicological importance but have not been studied in detail. This comprehensive approach that includes untargeted metabolomic and targeted bioanalytical sample analyses could be used to investigate toxicity of other compounds that pose preclinical or clinical development challenges in a pharmaceutical discovery and development.


Subject(s)
Acute Kidney Injury/chemically induced , Brain/metabolism , Indican/analysis , Metabolomics , Nicotinic Agonists/toxicity , Acute Kidney Injury/metabolism , Animals , Biomarkers , Indican/blood , Kidney/drug effects , Male , Mice , Organic Anion Transport Protein 1/physiology , Organic Anion Transporters, Sodium-Independent/physiology
5.
J Pharm Biomed Anal ; 52(4): 534-43, 2010 Aug 01.
Article in English | MEDLINE | ID: mdl-20149566

ABSTRACT

An LC-MS/MS method for simultaneous determination of hippuric acid (HA) and benzoic acid (BA) in monkey urine after direct injection was developed. Since HA and BA are endogenous compounds in urine, surrogate standards ((13)C(6)-hippuric and (13)C(6)-benzoic acid) were employed to generate calibration curves. l-Phenylalanine-ring-D5 served as an internal standard. Multiple reaction monitoring in the negative ionization mode with an APCI source was used for detection of all components in the assay. The developed method is intended for determination of HA and BA in the range of 0.25-250 and 0.1-100microg/ml, respectively. Weighted (1/x) quadratic regression (r(2)>0.99) was used to generate calibration curves. Precision and accuracy of the method were assessed by analyzing 3 quality control samples (concentrations at low, medium, and high range of calibration curve) prepared in monkey urine. Stability for 48h at room temperature and after 3 freeze-thaw cycles was also evaluated. The proposed method was successfully utilized for analysis of urine samples from female monkeys following the administration of everninomicin alone and in combination with gentamicin. The concentrations of endogenous HA and BA were calculated based on the peak area ratio of the analyte to the internal standard using a regression equation for corresponding surrogate standard.


Subject(s)
Benzoates/urine , Hippurates/urine , Tandem Mass Spectrometry/standards , Animals , Benzoates/standards , Biomarkers/urine , Chromatography, Liquid/methods , Chromatography, Liquid/standards , Drug Evaluation, Preclinical/methods , Drug Evaluation, Preclinical/standards , Female , Hippurates/standards , Macaca fascicularis , Mass Spectrometry/methods , Mass Spectrometry/standards , Tandem Mass Spectrometry/methods
6.
J Nat Prod ; 65(11): 1554-9, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12444676

ABSTRACT

Two new resveratrol tetramers, hopeaphenol A (1) and isohopeaphenol A (2), along with the known vaticaphenol A (3), were isolated from the stem bark of Vatica oblongifolia ssp. oblongifolia through bioassay-guided fractionation. The structures and their relative stereochemistry were determined by spectroscopic techniques. Compounds 1 and 3 demonstrated moderate activity against methicillin-resistant Staphylococcus aureus and Mycobacterium smegmatis.


Subject(s)
Ericales/chemistry , Plants, Medicinal/chemistry , Stilbenes/isolation & purification , Malaysia , Methicillin Resistance , Molecular Conformation , Molecular Structure , Mycobacterium smegmatis/drug effects , Nuclear Magnetic Resonance, Biomolecular , Plant Stems/chemistry , Resveratrol , Staphylococcus aureus/drug effects , Stilbenes/chemistry , Stilbenes/pharmacology
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