Design and synthesis of a novel series of orally active, selective somatostatin receptor 2 agonists for the treatment of type 2 diabetes.

The discovery of a novel series of ß-methyltryptophan (ß MeTrp) derivatives as selective and orally active non-peptide somatostatin receptor 2 (SSTR2) agonists for the treatment of Type 2 diabetes is described. In our previous research, Compound A, ß-MeTrp derivative with highly potent and selective SSTR2 agonistic activity IC50 (SSTR2/SSTR5)=0.3/>100 (nM), was identified asa drug candidate for treatment of Type 2 diabetes which lowers significantly plasma glucose level in Wistar fatty rats in its oral administrations. However, as serious increase in AUC and phospholipidosis (PLsis) were observed in its toxicological studies in rats, follow-up compounds were searched to avoid risk of PLsis with reference to their in vitro PLsis potentials evaluated on the basis of accumulation of phospholipids in HepG2 cells exposed to the compounds. It has been found that introduction of a carbonyl group onto the piperidine and piperazine or aniline moiety of compounds A and B reduced markedly the in vitro PLsis potentials. And further modification of the compounds and their evaluation led to a discovery of compounds 3k with lower in vitro PLsis potentials exhibiting lowering effect of hypoglycemia-induced glucagon secretion in SD rats (ED50=1.1mg/kg) and glucose excursion in meal tolerance test in Wistar fatty diabetic rats (MED=3.0mg/kg) in oral administrations. Compound 3k was selected asa new drug candidate of selective and orally active non-peptide SSTR2 agonists for treatment of Type 2 diabetes with low in vivo PLsis potential.

[Efficacy of oral balance gel for dry mouth in preoperative patients].

BACKGROUND: Following anticholinergic premedication and preoperative fasting, preoperative patients with a potential xerostomia have complaints associated with oral dryness. Xerostomia may lead to risk of mucosal burning and secondary infection. The purpose of this prospective study was to assess the effect of oral balance gel on dryness of the mouth in preoperative patients. METHODS: Thirty nine patients scheduled for elective surgery were randomly assigned to either of the group with or without using the oral balance gel. Severity of the dry mouth was assesed using a 4-point scale (0=none, 1=mild, 2=moderate, 3=severe) and diadochokinesis test was performed on the day before surgery and on arrival at the OR. RESULTS: Comparing results of the two stages, we found that patients with no treatment had significantly deteriorated state of dry mouth, but patients who had received the oral balance gel had no significantly worse dry mouth compared with the preoperative state. CONCLUSIONS: In this study, patients without the oral balance gel frequently reported oral symptons and oral dysfunction associated with xerostomia. We conclude that the use of oral balance gel in preoperative patients is effective for the prevention of dryness of the dry mouth.