Design, synthesis, and biological evaluation of novel somatostatin receptor subtype-2 agonists: Optimization for potency and risk mitigation of hERG and phospholipidosis.

Somatostatin receptors are members of G-protein coupled receptor superfamily. Receptors can be classified into five subtypes, SSTR1 to 5. The highly potent and orally active SSTR2 agonist 7, which had been identified by our group, was found out to have toxicological liabilities such as hERG inhibition and phospholipidosis (PLD).

Evaluation of Using Dogs to Predict Fraction of Oral Dose Absorbed in Humans for Poorly Water-Soluble Drugs.

Dogs have been widely used to study the oral absorption of a drug in drug discovery. However, there has been no quantitative validation of using dogs to predict the fraction of oral dose absorbed (Fa) in humans (Fa) for poorly water-soluble drugs. Here, we report the results of using dogs for quantitative Fa prediction, focusing on poorly water-soluble free acid and neutral drugs.

Effects of a prostagrandin EP4-receptor agonist ONO-AE1-329 on the left ventricular pressure-volume relationship in the halothane-anesthetized dogs.

Cardiac effects of a prostagrandin EP4-receptor agonist ONO-AE1-329 were assessed in the halothane-anesthetized dogs under the monitoring of left ventricular pressure-volume relationship, which were compared with those of clinically recommended doses of dopamine, dobutamine and milrinone (n=4-5 for each treatment). ONO-AE1-329 was intravenously administered in doses of 0.3, 1 and 3 ng/kg/min for 10 min with a pause of 20 min.

Cardiohemodynamic and electrophysiological effects of a selective EP4 receptor agonist ONO--AE1--329 in the halothane-anesthetized dogs.

Cardiovascular effects of a highly selective prostaglandin E2 type 4 (EP4) receptor agonist ONO-AE1-329 were assessed with the halothane-anesthetized dogs (n=6). ONO-AE1-329 was intravenously infused in three escalating doses of 0.3, 1 and 3ng/kg/min for 10min with a pause of 20min between the doses.

Why Can dl-Sotalol Prolong the QT Interval In Vivo Despite Its Weak Inhibitory Effect on hERG K(+) Channels In Vitro? Electrophysiological and Pharmacokinetic Analysis with the Halothane-Anesthetized Guinea Pig Model.

In order to bridge the gap of action of dl-sotalol between the human ether-a-go-go-related gene (hERG) K(+) channel inhibition in vitro and QT-interval prolongation in vivo, its electropharmacological effect and pharmacokinetic property were simultaneously studied in comparison with those of 10 drugs having potential to prolong the QT interval (positive drugs: bepridil, haloperidol, dl-sotalol, terfenadine, thioridazine, moxifloxacin, pimozide, sparfloxacin, diphenhydramine, imipramine and ketoconazole) and four drugs lacking such property (negative drugs: enalapril, phenytoin, propranolol or verapamil) with the halothane-anesthetized guinea pig model. A dose of each drug that caused 10 % prolongation of Fridericia-corrected QT interval (QTcF) was calculated, which was compared with respective known hERG K(+) IC50 value and currently obtained heart/plasma concentration ratio. Each positive drug prolonged the QTcF in a dose-related manner, whereas such effect was not observed by the negative drugs.

Discovery of new orally active prostaglandin D2 receptor antagonists.

To identify an orally available drug candidate, a series of 3-benzoylaminophenylacetic acids were synthesized and evaluated as prostaglandin D(2) (PGD(2)) receptor antagonists. Some of the compounds tested were found to exhibit excellent inhibitory activity against cAMP accumulation in human platelet rich plasma (hPRP), which is one of the indexes of DP antagonism. The optimization process including improvement of the physicochemical properties such as solubility, which may result in an improved pharmacokinetic (PK) profile, is presented.

Demonstration of docosahexaenoic acid as a bioavailability enhancer for CYP3A substrates: in vitro and in vivo evidence using cyclosporin in rats.

To investigate the pharmacokinetic interaction between cyclosporin A (CsA) and docosahexaenoic acid (DHA) in vivo, 5 mg/kg CsA was orally or intravenously coadministered with DHA (50-200 microg/kg) to rats. The effect of DHA on CYP3A activity was determined using rat liver microsomes in vitro. Moreover, the effect of DHA on P-glycoprotein (P-gp) function was examined using cultured Caco-2 cells in vitro.