A simple method for calculating the productivity of polyphenol separations by polymer-based chromatography.

A simple method for calculating the productivity of chromatography processes was proposed based on the iso-resolution curve concept. The model separation system was polyphenol separations by polystyrene divinylbenzene resins with the ethanol-water mixture mobile phase. The distribution coefficient K was determined as a function of ethanol concentration I by linear gradient elution experiments. The HETP-mobile phase velocity u curves were determined as a function of I. Using K and HETP, the iso-resolution curve was calculated, from which the productivity was determined as a function of I. It was found that there is an optimum I, where the highest productivity with the minimum amount of mobile phase consumption is obtained.

Discovery of a novel class of 1,3-dioxane-2-carboxylic acid derivatives as subtype-selective peroxisome proliferator-activated receptor alpha (PPARalpha) agonists.

A new series of 1,3-dioxane-2-carboxylic acid derivatives was synthesized and evaluated for agonist activity at human peroxisome proliferator-activated receptor (PPAR) subtypes. Structure-activity relationship studies led to the identification of 2-methyl-c-5-[4-(5-methyl-2-phenyl-1,3-oxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid 4b as a potent PPARalpha agonist with high subtype selectivity at human receptor subtypes. This compound exhibited a substantial hypolipidemic effect in type 2 diabetic KK-A(y) mice.

Structure-activity studies on 1,3-dioxane-2-carboxylic acid derivatives, a novel class of subtype-selective peroxisome proliferator-activated receptor alpha (PPARalpha) agonists.

A series of 1,3-dioxane carboxylic acid derivatives was synthesized and evaluated for human PPAR transactivation activity. Structure-activity relationships on the phenyloxazole moiety of the lead compound 3 revealed that the introduction of small hydrophobic substituents at the 4-position of the terminal phenyl ring increased the PPARalpha agonist activity, and that the oxazole heterocycle was essential to the maintenance of both potency and PPARalpha subtype-selectivity. This investigation led to the identification of 14d (NS-220) and 14i as highly potent and selective human PPARalpha agonists. In KK-A(y) type 2 diabetic mice, these compounds significantly lowered plasma triglyceride and very-low-density plus low-density lipoprotein cholesterol levels while simultaneously raising HDL cholesterol levels. Our results suggest that highly potent and subtype-selective PPARalpha agonists will be promising drugs for the treatment of metabolic disorders in type 2 diabetes.

Structure-activity relationship study on the 6-membered heteroaromatic ring system of diphenylpyrazine-type prostacyclin receptor agonists.

A series of prostacyclin receptor agonists was prepared by modifying the central heteroaromatic ring of lead compound 2, and a docking study was performed to investigate their structure-activity relationships by using a homology-modeled structure of the prostacyclin receptor. Compound 2 and its derivatives could be docked to the prostacyclin receptor in two ways depending on the position of the nitrogen atom within the heteroaromatic ring. Furthermore, hydrogen bonding between the nitrogen atom in the heteroaromatic ring and the hydroxyl group of Ser20 or Tyr75 of the receptor appears to be important for the potent expression of biological activity.

Structure-activity studies on diphenylpyrazine derivatives: a novel class of prostacyclin receptor agonists.

To develop nonprostanoid prostacyclin receptor agonists with a high degree of metabolic resistance and an extended duration of action, a novel series of diphenylpyrazine derivatives was synthesized and evaluated for their inhibition of ADP-induced human platelet aggregation. Structure-activity relationship studies on the side chain containing the carboxylic acid moiety of the lead compound 5c showed that the length of the linker and the presence of the concatenating nitrogen atom adjacent to the pyrazine ring are critical for the antiaggregatory activity. This study led to the discovery of 2-amino-5,6-diphenylpyrazine derivatives 8c, 15a, and 15b, which showed potent inhibition of platelet aggregation with IC(50) values of 0.2 microM. Among these compounds, 15b is an orally available and long-lasting prostacyclin receptor agonist which is promising for the treatment of various vascular diseases.

Design and synthesis of 3-substituted benzamide derivatives as Bcr-Abl kinase inhibitors.

A series of 3-substituted benzamide derivatives structurally related to STI-571 (imatinib mesylate), a Bcr-Abl tyrosine kinase inhibitor used to treat chronic myeloid leukemia (CML), was prepared and evaluated for antiproliferative activity against the Bcr-Abl-positive leukemia cell line K562. About ten 3-halogenated and 3-trifluoromethylated benzamide derivatives were identified as highly potent Bcr-Abl kinase inhibitors. One of these, NS-187 (9b), is a promising new candidate Bcr-Abl inhibitor for the therapy of STI-571-resistant chronic myeloid leukemia.