Design, synthesis, and biological evaluation of aryl N-methoxyamide derivatives as GPR119 agonists.

A series of N-methoxyamide derivatives was identified and evaluated as GPR119 agonists. Several N-methoxyamides with thienopyrimidine and pyridine scaffolds showed potent GPR119 agonistic activities. Among them, compound 9c displayed good in vitro activity and potency. Moreover, compound 9c lowered glucose excursion in mice in an oral glucose tolerance test and increased GLP-1 secretion in intestinal cells.

Experimental and Computational Study of an Unexpected Iron-Catalyzed Carboetherification by Cooperative Metal and Ligand Substrate Interaction and Proton Shuttling.

An iron-catalyzed cycloisomerization of allenols to deoxygenated pyranose glycals has been developed. Combined experimental and computational studies show that the iron complex exhibits a dual catalytic role in that the non-innocent cyclopentadienone ligand acts as proton shuttle by initial hydrogen abstraction from the alcohol and by facilitating protonation and deprotonation events in the isomerization and demetalation steps. Molecular orbital analysis provides insight into the unexpected and selective formation of the 3,4-dihydro-2H-pyran.

Synthesis and biological evaluation of thienopyrimidine derivatives as GPR119 agonists.

A series of thienopyrimidine derivatives was synthesized and evaluated for their GPR119 agonistic ability. Several thienopyrimidine derivatives containing R(1) and R(2) substituents displayed potent GPR119 agonistic activity. Among them, compound 5d, which is a prototype, showed good in vitro activity with an EC50 value of 3 nM and human and rat liver microsomal stability. Compound 5d exhibited no CYP inhibition and induction, Herg binding, or mutagenic potential. Compound 5d showed increase insulin secretion in beta TC-6 cell and lowered the glucose excursion in mice in an oral glucose-tolerance test.

Filtering Bleb Size in the Early Postoperative Period Affects the Long-term Surgical Outcome after Trabeculectomy.

PURPOSE: To investigate whether postoperative filtering bleb size affects the surgical outcome after trabeculectomy. METHODS: In this study, we retrospectively reviewed 145 medically uncontrolled glaucoma patients with intraocular pressure (IOP) values >21 mmHg before surgery and data from ≥2 years of follow-up. Postoperative IOP, filtering bleb size including extent and height, and other clinical factors were measured after trabeculectomy. We divided bleb extent into quadrants and bleb height by 0.5 intervals of corneal thickness. The main outcome measure was surgical success. We confirmed complete success when the IOP was ≤21 mmHg and decreased by >20% from baseline without medication or additional procedures. Qualified success used the same criteria but allowed for medication or additional procedures. Cases with reoperation or two consecutive IOP measurements <6 mmHg were considered failures. RESULTS: A total of 145 eyes of 145 patients was included. The average observation period was 30.8 ± 10.9 months. During multivariate Cox regression analysis, a larger extent of filtering bleb revealed significantly low hazard ratios in both complete and surgical success (0.509 and 0.494, respectively); however, there was no significant relationship between bleb height and surgical outcome. CONCLUSIONS: The extent of the filtering bleb was associated with surgical outcomes of trabeculectomy in glaucoma patients.

Surgical outcomes of unilateral lateral rectus recession versus recess-resect in children with convergence insufficiency type intermittent exotropia.

To determine the efficacy of unilateral lateral rectus recession (ULR) for convergence insufficiency-type intermittent exotropia (CI-type IXT), we compared surgical outcomes following ULR and recess‒resect (RR) procedures for CI-type IXT. In this retrospective study, medical records of 57 children who underwent ULR (n = 30) or RR (n = 27) for CI-type IXT of less than 25 PD at distance with a postoperative follow-up of 6 months or more were reviewed. Surgical success was defined as an alignment between 10 PD exodeviation and 5 PD esodeviation at distance and near fixation. The postoperative exodeviation showed no significant difference between the two groups at the last follow-up. A significant reduction in the mean near-distance difference was achieved postoperatively in both groups: from 5.4 PD preoperatively to 2.5 at last follow-up after ULR, and from 8.2 to 2.4 after RR (both p = 0.001). However, this difference between ULR and RR was not statistically significant (p > 0.05). The success rate at the last follow-up was 63.3% for ULR and 70.4% for RR (p = 0.574). ULR was found to be an effective treatment for CI-type IXT, with similar surgical outcomes to RR.

Border tissue morphology is associated with macular ganglion cell thickness in open-angle glaucoma.

Externally oblique border tissue (EOBT) configuration is topographically associated with glaucomatous damage in the optic nerve head. We investigated the relationship between the EOBT characteristics and macular retinal ganglion cell (RGC) thickness in patients with open-angle glaucoma (OAG). A total of 149 eyes with OAG that had an EOBT observed on optical coherence tomography exams were included. After determining the maximum EOBT length and angular location of the maximal EOBT length, we analyzed their correlation with macular ganglion cell inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) thickness. The macular GCIPL and pRNFL thickness were compared based on the angular location of the longest EOBT, and their association was assessed using multivariable regression analysis. Maximum EOBT length was significantly correlated with macular GCIPL thickness, but not with pRNFL thickness. Macular GCIPL was thinnest in eyes with EOBT located in a temporal direction to the optic disc. Longer maximum EOBT and temporally elongated EOBT were independently associated with a thinner macular GCIPL in the multivariable regression analysis. These suggest that temporal elongation of the EOBT may increase the stress and strain on the RGCs derived from the macula and make RGCs more susceptible to glaucoma-inducing damage.

Chemoselective Luche-Type Reduction of α,ß-Unsaturated Ketones by Magnesium Catalysis.

The chemoselective reduction of α,ß-unsaturated ketones by use of an economic and readily available Mg catalyst has been developed. Excellent yields for a wide range of ketones have been achieved under mild reaction conditions, short times, and low catalyst loadings (0.2-0.5 mol %).

Discovery of Novel Pyruvate Dehydrogenase Kinase 4 Inhibitors for Potential Oral Treatment of Metabolic Diseases.

Pyruvate dehydrogenase kinase 4 (PDK4) activation is associated with metabolic diseases including hyperglycemia, insulin resistance, allergies, and cancer. Structural modifications of hit anthraquinone led to the identification of a new series of allosteric PDK4 inhibitors. Among this series, compound 8c showed promising in vitro activity with an IC50 value of 84 nM. Good metabolic stability, pharmacokinetic profiles, and possible metabolites were suggested. Compound 8c improved glucose tolerance in diet-induced obese mice and ameliorated allergic reactions in a passive cutaneous anaphylaxis mouse model. Additionally, compound 8c exhibited anticancer activity by controlling cell proliferation, transformation, and apoptosis. From the molecular docking studies, compound 8c displayed optimal fitting in the lipoamide binding site (allosteric) with a full fitness, providing a new scaffold for drug development toward PDK4 inhibitors.

Sustainable Alkylation of Unactivated Esters and Amides with Alcohols Enabled by Manganese Catalysis.

The first example of manganese-catalyzed C-alkylation of the carboxylic acid derivatives is reported. The bench-stable homogeneous manganese complex enables the transformation of the renewable alcohol and carboxylic acid derivative feedstock to higher value esters and amides. The reaction operates via hydrogen autotransfer and ideally produces water as the only side product. Importantly, aliphatic-, benzylic-, and heterocyclic-containing alcohols can be used as alkylating reagents, eliminating the need for mutagenic alkyl halides.

Cooperative Metal-Ligand Catalyzed Intramolecular Hydroamination and Hydroalkoxylation of Allenes Using a Stable Iron Catalyst.

A new iron-catalyzed chemoselective intramolecular hydroamination and hydroalkoxylation of the readily available α-allenic amines and alcohols to valuable unsaturated 5-membered heterocycles, 2,3-dihydropyrrole and 2,3-dihydrofuran, is reported. Effective selectivity control is achieved by a metal-ligand cooperative activation of the substrates. The mild reaction conditions and the use of low amounts of an air and moisture stable iron catalyst allow for the hydrofunctionalization of a wide range of allenes bearing different functional groups in good yields in the absence of base or any sensitive additives.

[Predictors of nursing service need for nursing homes residents].

PURPOSE: The purposes of this study were to explore the functional status of elderly residents and to analyze time use, and finally identify factors to predict nursing care needs in relation to functional status and health related variables. METHODS: In this study a descriptive-correlational design was used. Functional status of participants was obtained through interviews, and nursing care time was examined using a 1 min time-motion study with a standardized instrument developed by Korea Long-Term Care Planning Committee (2005). RESULTS: The mean total functional score was 65 (range 28-125) and mean total nursing care time was 144.15 min per day. There were significant positive relationships between total nursing care time, marital status, back pain, dementia, and vision impairment. Multiple regression analyses showed that a liner combination of number of illnesses, types of primary disease, ADL, IADL, cognitive function, nursing demand, and rehabilitation demand explained 42.8% of variance of total nursing time. ADL (beta=-.533) was the most significant predictor of nursing service need. CONCLUSION: Identifying factors that result in variations of service need has implications for adequate nursing service, estimation of optimum nurse to patient ratio, quality of care and patient safety.