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The optimization of our lead GK activator 2a to 3-[(1S)-2-hydroxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]-N-1,3-thiazol-2-ylbenzamide (6g), a potent GK activator with good oral availability, is described, including to uncouple the relationship between potency and hydrophobicity. Following oral administration, this compound exhibited robust glucose lowering in diabetic model rodents.

The osteoinductive activity induced by recombinant human BMP-2 (rhBMP-2) blunts proportionately as the recipient ages. In order to compensate for this bluntness administration of fibroblast growth factor-2 (FGF-2) has been considered. The aim of this study was to determine whether FGF-2 administration augments osteoinductive activity caused by rhBMP-2 and to evaluate the effect of aging on bone formation induced by coadministration of rhBMP-2 and FGF-2. Sixty-four Wistar strain male rats of 8-week-old (prepubertal) and 16-week-old (postpubertal) received bone defects bilaterally in the parietal bone and the defects were filled by a polylactic acid polyglycolic acid copolymer/gelatin sponge (PGS) impregnated with rhBMP-2 plus 0 ng, 25 ng, and 250 ng FGF-2 (n=10 in each). At 2 weeks after grafting, the new bone volume seemed to be larger in the rhBMP-2+FGF-2 groups than in the rhBMP-2 alone group. At 4 weeks, the new bone formation was linked to the adjacent original bone. In the prepubertal rats, all newly formed bone was similarly calcified. In the postpubertal rats, only the rhBMP-2+25 ng FGF-2 group showed this higher degree of calcification. At 2 weeks, alkaline phosphatase (ALP) activity in the rhBMP-2+25 ng FGF-2 group was significantly (p

A novel series of (2R)-2-[(1R)-3, 3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamides was designed and synthesized based on the structure and biological profiles of an active metabolite 2 of our prototype muscarinic M(3) receptor selective antagonist 1, to develop a potent, long-acting, orally active M(3) antagonist for the treatment of urinary tract disorders, irritable bowel syndrome, and respiratory disorders. Investigation of (2R)-2-[(1R)-3, 3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamides containing a phenyl or heterocyclic ring as the piperidinyl side chain in place of the 4-methyl-3-pentenyl moiety of 15a revealed that this acid moiety was a versatile template for improving the selectivity for M(3) over M(2) receptors in comparison with the corresponding cyclopentylphenylacetic acid group. However, since the in vitro metabolic stability of these analogues was insufficient compared with that of 2, further derivatization was performed by introducing an appropriate hydrophilic group into the phenyl or 2-pyridyl ring. Thus, the 1-(6-aminopyridin-2-ylmethyl)piperidine analogue 15y exhibiting 190-fold selectivity for M(3) receptors (K(i) = 2.8 nM) over M(2) receptors (K(i) = 530 nM) in a human binding assay and good in vitro metabolic stability in dog and human hepatic microsomes was identified. This compound has excellent oral activity at 4 h after oral dosing (1 mg/kg), inhibiting methacholine-induced bronchoconstriction in dogs, and may be useful in clinical situations in which M(3) over M(2) selectivity is desirable.

In the course of developing a metabolically stable M3 receptor antagonist from the prototype antagonist, J-104129 (1), introduction of certain substituents into the cyclopentane ring of 1 was found to be effective not only in improving metabolic stability but also in greatly enhancing the subtype selectivity. Among the cyclopentane analogues, sulfonamide derivatives (10f) and (10g) displayed 160- and 310-fold selectivity for M3 over M2 receptors, and both were significantly more selective than the prototype antagonist (120-fold). Subsequent derivatization of the sulfonamide series led to the highly selective M3 receptor antagonists (10h, 10i and 10j) with >490-fold selectivity for M3 over M2 receptors. Among them, p-nitrophenylsulfonamide (J-107320, 10h) exhibited 1100-fold selectivity for M3 receptors (Ki = 2.5 nM) over M2 receptors (Ki = 2800 nM) in the human muscarinic receptor binding assay using [3H]-NMS as a radio ligand.

Glucokinase activators (GKAs) are currently under investigation as potential antidiabetic agents by many pharmaceutical companies. Most of GKAs reported previously possess N-aminothiazol-2-yl amide moiety in their structures because the aminothiazole moiety interacts with glucokinase (GK) and shows strong GK activation. During the development of N-aminothiazol-2-yl amide derivatives, we identified a bioactivation and metabolic liability of 2-aminothizole substructure of GKA 3 by assessing covalent binding, metabolites in liver microsomes and glutathione (GSH) trap assay.

The correction of a severe maxillary protrusion in an adult by distal movement of the maxillary molars has been one of the most difficult biomechanical problems in orthodontics. This article reports on the treatment of an adult case of severe maxillary protrusion and a large overjet treated with a skeletal anchorage system. A female patient, age 22 years and 3 months, complained of the difficulty of lip closure due to severe maxillary protrusion with a gummy smile. Overjet and overbite were +7.6 mm and −0.9 mm, respectively. She had a history of orthodontic treatment in which her maxillary first premolars were extracted. In order to conduct distal movement of the maxillary molars, anchor plates were placed in the zygomatic process. After achieving a Class I molar relationship, retraction and intrusion of the maxillary incisors were performed. After a 2-year treatment, an acceptable occlusion was achieved with a Class I molar relationship. Her convex facial profile with upper lip protrusion was considerably improved, and the lips showed less tension in lip closure. After a 2-year retention period, an acceptable occlusion was maintained without recurrence of maxillary protrusion, indicating a stability of the occlusion. The result of this treatment indicated that skeletal anchorage is of great importance as a remedy for achieving intrusion and retraction of the maxillary incisors in cases of severe maxillary protrusion with a patient who had previous orthodontic treatment.

This study reports the treatment of an adolescent patient with dilacerated maxillary incisor. She complained of severe crowding with a high-positioned left upper canine. Her left central incisor had been impacted and moved to proper position at the age of eight years, resulting in a severe root dilaceration. To avoid any progression of root dilacerations and resorption in the maxillary incisor, maxillary lateral expansion and molar distalization plus multibracket appliance were selected as the best nonextraction treatment plan. The maxillary expansion and molar distalization should provide adequate space for the correction of the severe crowding, and treatment with a multibracket appliance was initiated. After a 17-month treatment with a multibracket appliance, an acceptable occlusion was achieved with a Class I molar relationship. An acceptable occlusion was maintained without recurrence of the crowding and impairment of the dilacerated root in the maxillary incisor during three years of retention. It is emphasized that careful planning is required to avoid any progression of the root dilaceration and resorption through orthodontic treatment. A shortening of the period of applying orthodontic force on the dilacerated incisor and avoidance of tooth extraction will minimize the risk factors.

Control of the height of posterior dentoalveolar regions is of great importance for the correction of skeletal open bite. Traditionally, second premolar extraction facilitates the closure of open bite by inducing a counterclockwise mandibular rotation without molar intrusion. This article reports treatment for a 24-year six-month-old female patient with an open bite and large anterior facial height. She complained of occlusal disturbances and difficulty of lip closure because of the open bite. Overjet and overbite were +3.0 mm and -3.0 mm, respectively. To correct open bite and crowding, the bilateral extraction of the maxillary and mandibular second premolars plus multibracket appliances for mesial movement of the molars was selected as the treatment plan. After a two-year treatment, an acceptable occlusion was achieved, the lower anterior facial height was decreased, and the lips showed less tension in a lip closure. An acceptable occlusion was maintained without recurrence of the open bite during a three-year retention period, indicating a long-term stability of the occlusion. The results of this treatment indicated that the correction of open bite with no or less molar intrusion or incisor extrusion is of great importance for achieving stable occlusion and avoiding the relapse of open bite.

Optimization of the amine part of our original muscarinic M(3) receptor antagonist 1 was performed to identify M(3) receptor antagonists that are superior to 1. Compounds carrying a variety of diamine moieties without hydrophobic substituent on the nitrogen atom were screened against the binding affinity for the M(3) receptor and the selectivity for M(3) over the M(1) and M(2) receptors. This process led to a 4-aminopiperidinamide (2l) with a K(i) value of 5.1 nM and with a selectivity of the M(3) receptor that was 46-fold greater than that of the M(2) receptor. Further derivatization of 2l by inserting a spacer group or by incorporating alkyl group(s) into the amine part resulted in the identification of an 4-(aminoethyl)piperidinamide 2l-b with a K(i) value of 3.7 nM for the M(3) receptor and a selectivity for the M(3) receptor that was 170-fold greater than that of the M(2) receptor.

Alterations in the pattern of gene expression were studied during differentiation of the human embryonal carcinoma (EC) cell line NEC14. NEC14 cells can be induced to differentiate by the addition of 10-2 M N,N′-hexamethylene-bis-acetamide (HMBA). The efficiency of DNA transfection of undifferentiated and differentiated NEC14 cells was compared by measuring the activities of endogenous and exogenously introduced promoters for the beta-actin gene and heat shock protein 70 gene. The results indicated that the efficiency was not significantly different in cells of these two states. Under the conditions used, all the viral enhancer-promoters tested showed very little or no activity in undifferentiated cells, but activities of SV40, BKV, adenovirus and RSV enhancers were greatly increased after differentiation. Activities of these viral enhancers in differentiated cells were completely repressed by cotransfection with the adenovirus E1A gene. An E1 A-inducible promoter of the adenovirus E2 gene showed stronger activity in differentiated than in undifferentiated cells, and was not activated efficiently by cotransfection with the E1 A gene in either undifferentiated or differentiated cells. These results indicate that factor(s) regulating activities of various enhancer-promoters in NEC14 cells is or are different from E1A-like factor(s) present in mouse EC F9 cells.