Synthesis and biological evaluation of novel chiral diazepine derivatives as bombesin receptor subtype-3 (BRS-3) agonists incorporating an antedrug approach.

Novel compounds based on the lead BRS-3 agonists from our HTS compounds 2a and 2b have been synthesized with the focus on obtaining peripheral BRS-3 agonists. To identify potent anti-obesity compounds without adverse effects on the central nerve system, a labile carboxylic ester with an antedrug functionality was introduced onto the terminal position. Through the extensive synthetic exploration and the pharmacokinetic studies of oral administration in mice, the phenol ester 17c was selected due to the most suitable pharmacological profile. In the evaluation of food intake suppression in B6 mice, 17c showed significant in vivo efficacy and no clear adverse effect on heart rate and blood pressure change in dog iv infusion. Our study paved the way for development of anti-diabetes and obesity drugs with a safer profile.

Relationship between refractive index and fatty acid composition by gas chromatography and near-infrared fiber-optic method in bovine fat.

The causes of the difference in fatty acid composition between gas chromatography (GC) and near-infrared fiber-optic method (NIR) in bovine fat and their countermeasures were studied using absolute values of refractive index. Using intermuscular fat from 45 crossbreeds, refractive index was measured by using a refractometer, and saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) were measured by NIR and GC. The correlation coefficients between GC and NIR in SFA and MUFA, as well as those between refractive index and GC or NIR (in SFA and MUFA), were all greater than or equal to 0.8 (p < 0.01). In samples with 3% or more difference between GC and NIR in SFA and MUFA, GC and NIR values were often located in opposite directions to the regression lines with regard to refractive index. GC reanalysis on these samples slightly increased the correlation coefficient between GC and refractive index and reduced the difference between GC and NIR by 1%-2%. Results indicate that measurement errors in GC and NIR are related to their more than 3% difference, and GC reanalysis based on refractive index may improve its accuracy.

Discovery of novel tricyclic compounds as squalene synthase inhibitors.

In the present article, we have reported the design, synthesis, and identification of highly potent benzhydrol derivatives as squalene synthase inhibitors (compound 1). Unfortunately, the in vivo efficacies of the compounds were not enough for acquiring the clinical candidate. We continued our investigation to obtain a more in vivo efficacious template than the benzhydrol template. In our effort, we focused on a benzoxazepine ring and designed a new tricyclic scaffold by the incorporation of heterocycle into it. Prepared pyrrolobenzoxazepine derivatives showed further efficient in vitro and in vivo activities.

Discovery of a new 2-aminobenzhydrol template for highly potent squalene synthase inhibitors.

To obtain small and efficient squalene synthase inhibitors, a flexible 2-aminobenzhydrol open form structure was designed and showed potent inhibitory activity comparable to 4,1-benzoxazepin compounds. Further chemical modification led to the discovery of a novel template with a strong squalene synthase inhibitory activity, and its basic structure-activity relationship was revealed. The X-ray crystallographic data of compound 12 bound to the active site of squalene synthase provided an important insight into the binding mode of this alternative template that formed 11-membered ring conformations with an intramolecular hydrogen bond.

Discovery of atrop fixed alkoxy-aminobenzhydrol derivatives: novel, highly potent and orally efficacious squalene synthase inhibitors.

We have recently reported the discovery of the new benzhydrol template, which has a highly potent inhibitory activity for squalene synthase, as typified by compound 1 (SSI IC(50)=0.85 nM). However, it was composed of a pair of easy rotatable atropisomers. In the effort to fix the isomerization, a highly potent alkoxy-aminobenzhydrol scaffold was developed. Some of these acquired compounds demonstrating strong cholesterol synthesis inhibitory activities in a rat hepatic cell. Moreover, two of the series compounds exhibited specific plasma lipid-lowering effects in in vivo animal models.

Constructing second-order accurate confidence intervals for communalities in factor analysis.

In an effort to find accurate alternatives to the usual confidence intervals based on normal approximations, this paper compares four methods of generating second-order accurate confidence intervals for non-standardized and standardized communalities in exploratory factor analysis under the normality assumption. The methods to generate the intervals employ, respectively, the Cornish-Fisher expansion and the approximate bootstrap confidence (ABC), and the bootstrap-t and the bias-corrected and accelerated bootstrap (BC(a)). The former two are analytical and the latter two are numerical. Explicit expressions of the asymptotic bias and skewness of the communality estimators, used in the analytical methods, are derived. A Monte Carlo experiment reveals that the performance of central intervals based on normal approximations is a consequence of imbalance of miscoverage on the left- and right-hand sides. The second-order accurate intervals do not require symmetry around the point estimates of the usual intervals and achieve better balance, even when the sample size is not large. The behaviours of the second-order accurate intervals were similar to each other, particularly for large sample sizes, and no method performed consistently better than the others.

Discovery of DF-461, a Potent Squalene Synthase Inhibitor.

We report the development of a new trifluoromethyltriazolobenzoxazepine series of squalene synthase inhibitors. Structure-activity studies and pharmacokinetics optimization on this series led to the identification of compound 23 (DF-461), which exhibited potent squalene synthase inhibitory activity, high hepatic selectivity, excellent rat hepatic cholesterol synthesis inhibitory activity, and plasma lipid lowering efficacy in nonrodent repeated dose studies.