Discovery of a Novel Highly Selective Histamine H4 Receptor Antagonist for the Treatment of Atopic Dermatitis.

The histamine H4 receptor (H4R), a member of the G-protein coupled receptor family, has been considered as a potential therapeutic target for treating atopic dermatitis (AD). A large number of H4R antagonists have been disclosed, but no efficient agents controlling both pruritus and inflammation in AD have been developed yet. Here, we have discovered a novel class of orally available H4R antagonists showing strong anti-itching and anti-inflammation activity as well as excellent selectivity against off-targets.

P-Glycoprotein, not BCRP, Limits the Brain Uptake of [(18)F]Mefway in Rodent Brain.

Purpose: The aim of this study was to determine whether the brain uptake of [(18)F]Mefway is influenced by the action of P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) in rodents.

Procedures: [(18)F]Mefway was applied to rats pharmacologically inhibited with tariquidar (TQD) and to genetically disrupted mice.

Results: Pretreatment of TQD results in 160% higher hippocampal uptake compared with control rats.

Determination of a novel phosphodiesterase4 inhibitor, 3-[1-(3cyclopropylmethoxy-4-difluoromethoxybenzyl)-1H-pyrazol-3-yl]-benzoic acid (PDE-423) in rat plasma using liquid chromatography-tandem mass spectrometry.

A method for determining a novel phosphodiesterase-4 inhibitor, 3-[1-(3cyclopropylmethoxy-4-difluoromethoxybenzyl)-1H-pyrazol-3-yl]-benzoic acid (PDE-423), in rat plasma was developed and validated using liquid chromatography-tandem mass spectrometry for further pharmacokinetic study for development as a novel anti-asthmatic drug. PDE-423 in the concentration range of 0.02-10 µg/mL was linear with a correlation coefficient of >0.

Preclinical pharmacokinetic characterization of 2-(4-(4-(5-(2-phenyl-5-(trifluoromethyl)oxazole-4-carboxamido)-1H-benzo[d]imidazol-2-yl)phenyl)cyclohexyl) acetic acid, a novel DGAT-1 inhibitor.

1. A novel diacylglyceride acyltransferase-1 (DGAT-1) inhibitor, 2-(4-(4-(5-(2-phenyl-5-(trifluoromethyl) oxazole-4-carboxamido)-1H-benzo[d]imidazol-2-yl)phenyl)cyclohexyl) acetic acid (KR-69232), was synthesized for a potential therapeutic use against several metabolic disorders, such as obesity, insulin resistance, and type II diabetes, characterized by excessive triglycerides (TGs) in the blood. 2.

Pharmacokinetic characterization of the novel TAZ modulator TM-25659 using a multicompartment kinetic model in rats and a possibility of its drug-drug interactions in humans.

This study evaluated the pharmacokinetics of the novel TAZ modulator TM-25659 in rats following intravenous and oral administration at dose ranges of 0.5-5 mg/kg and 2-10 mg/kg, respectively. Plasma protein binding, plasma stability, liver microsomal stability, CYP inhibition, and transport in Caco-2 cells were also evaluated.