Preclinical metabolism and the disposition of vornorexant/TS-142, a novel dual orexin 1/2 receptor antagonist for the treatment of insomnia.

We investigated the metabolism and disposition of vornorexant, a novel dual orexin receptor antagonist, in rats and dogs, and clarified in vitro metabolite profiles in humans. Furthermore, we investigated the pharmacokinetics of active metabolites in rats and dogs and their CNS distribution in rats to elucidate its contribution to drug efficacy. [ C]vornorexant was rapidly and mostly absorbed after the oral administration in rats and dogs.

Lead generation from N-[benzyl(4-phenylbutyl)carbamoyl]amino acid as a novel LPA antagonist for the treatment of systemic sclerosis.

Lysophosphatidic acid (LPA), a bioactive phospholipid, binds to the G protein-coupled LPA receptor on the surfaces of immune cells, to promote progression of fibrosis of the skin and organs through inducing infiltration of immune cells into tissues, chemokine production, inflammatory cytokine production, and fibroblast transformation. Anti-fibrotic effects of LPA blockade have been reported in animal models of scleroderma and scleroderma patients. In the study reported herein, we identified the novel urea compound 5 as a hit compound with LPA1 antagonist activity from our in-house library and synthesized the lead compound TP0541640 (18) by structural transformation utilizing a structure-based drug design (SBDD) approach.

Chiral LC-MS/MS method for the simultaneous determination of (R,S)-ketamine, (R,S)-norketamine, and (2R,6R;2S,6S)-hydroxynorketamine in mouse plasma and brain.

A convenient LC-MS/MS assay method to simultaneously and sensitively determine (R,S)-ketamine (Ket), (R,S)-norketamine (NK), and (2R,6R;2S,6S)-hydroxynorketamine (HNK) enantiomers in plasma and brain from mice was developed. This method enables the chiral separations of these six enantiomers in one analysis by constructing a column-switching system composed of one achiral column and two chiral columns with a relatively short analysis time (17 min). The chromatography involves the separation of (2R,6R;2S,6S)-HNK from (R,S)-Ket and (R,S)-NK on an octadecyl-silica column, followed by chiral separations on a CHIRALPAK AY-RH column for (2R,6R;2S,6S)-HNK or on a CHIRALPAK AS-RH column for the other analytes.

Discovery of Aryloxyphenyl-Heptapeptide Hybrids as Potent and Selective Matrix Metalloproteinase-2 Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis.

Matrix metalloproteinase-2 (MMP2) is a zinc-dependent endopeptidase that plays important roles in the degradation of extracellular matrix proteins. MMP2 is considered to be an attractive target for the treatment of various diseases such as cancer, arthritis, and fibrosis. In this study, we have developed a novel class of MMP2-selective inhibitors by hybridizing the peptide that binds to a zinc ion and S2-S5 pockets with small molecules that bind to the S1' pocket.

AMPA Receptor Activation-Independent Antidepressant Actions of Ketamine Metabolite (S)-Norketamine.

Background: Ketamine, an N-methyl-D-aspartate receptor antagonist, exerts robust antidepressant effects in patients with treatment-resistant depression. The precise mechanisms underlying ketamine's antidepressant actions remain unclear, although previous research suggests that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) activation plays a role. We investigated whether (S)-norketamine and (R)-norketamine, the two main metabolites of (R,S)-ketamine, also play a significant role in ketamine's antidepressant effects and whether the effects are mediated by AMPAR.

No Sex-Specific Differences in the Acute Antidepressant Actions of (R)-Ketamine in an Inflammation Model.

Background: Although previous reports suggest sex-specific differences in the antidepressant actions of (R,S)-ketamine, these differences in the antidepressant actions of (R)-ketamine, which is more potent than (S)-ketamine, are unknown.

Methods: Saline or (R)-ketamine was administered 23 hours post lipopolysaccharide administration to adult male or female mice. Subsequently, antidepressant effects were assessed using a forced swimming test.

(2R,6R)-Hydroxynorketamine is not essential for the antidepressant actions of (R)-ketamine in mice.

(R,S)-Ketamine has rapid and sustained antidepressant effects in depressed patients. Although the metabolism of (R,S)-ketamine to (2 R,6 R)-hydroxynorketamine (HNK), a metabolite of (R)-ketamine, has been reported to be essential for its antidepressant effects, recent evidence suggests otherwise. The present study investigated the role of the metabolism of (R)-ketamine to (2 R,6 R)-HNK in the antidepressant actions of (R)-ketamine.

A rapid and sensitive chiral LC-MS/MS method for the determination of ketamine and norketamine in mouse plasma, brain and cerebrospinal fluid applicable to the stereoselective pharmacokinetic study of ketamine.

A novel method for the rapid and sensitive chiral determination of ketamine and norketamine in mouse plasma, brain and cerebrospinal fluid (CSF) was developed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). This method reduces the required matrix volume, compared with a previously reported chiral assay method for ketamine and norketamine. The method involves the deproteinization of a small amount of biological matrix (corresponding to 5μL of plasma, 10mg of brain, or 2.

Antidepressant Potential of ()-Ketamine in Rodent Models: Comparison with ()-Ketamine.

The rapid-acting and long-lasting antidepressant effects of ()-ketamine have recently gained much attention. Although ()-ketamine has been studied as an active isomer, recent evidence suggests that ()-ketamine exhibits longer-lasting antidepressant effects than ()-ketamine in rodents. However, the antidepressant potential of ()-ketamine has not been fully addressed.

Gene expression profiles of ATP-binding cassette transporter A and C subfamilies in mouse retinal vascular endothelial cells.

The purpose of this study was to quantify gene expression levels of the ATP-binding cassette (ABC) transporter A and C subfamilies ABCA1-A9, and ABCC1-6/Mrp1-6, C10/Mrp7 in mouse retinal vascular endothelial cells (RVEC) using a combination of a magnetic isolation method for mouse RVEC and real-time quantitative PCR analysis. The transcript level of endothelial cell markers, such as CD31, Tie-2, claudin-5, occludin, ABCB1a/mdr1a, and ABCG2, were more than 20-fold higher than those in the non-RVEC fraction, suggesting that RVEC in the RVEC fraction are concentrated at least 20-fold compared with those of the non-RVEC fraction. In the ABCA1 to A9 families, the transcript level of ABCA3 and A9 in the RVEC fraction was 1.