A clinical study comparing ultrasound-measured pyloric antrum cross-sectional area to computed tomography-measured gastric content volume to detect high-risk stomach in supine patients undergoing emergency abdominal surgery.

The main aim of this study was to assess whether the ultrasound examination and measurement of the pyloric antral cross-sectional area (antral-CSA) in the supine position could be useful to diagnose a full stomach using a computed tomography (CT) as a comparator in emergency patients. Immediately before general anesthesia induction in patients undergoing emergency abdominal surgery, antral-CSA was measured and the volume of the gastric contents was evaluated via ultrasound in the supine position. Gastric content volume was also calculated from a CT image taken prior to the operation.

Structures of the PKC-iota kinase domain in its ATP-bound and apo forms reveal defined structures of residues 533-551 in the C-terminal tail and their roles in ATP binding.

Protein kinase C (PKC) plays an essential role in a wide range of cellular functions. Although crystal structures of the PKC-theta, PKC-iota and PKC-betaII kinase domains have previously been determined in complexes with small-molecule inhibitors, no structure of a PKC-substrate complex has been determined. In the previously determined PKC-iota complex, residues 533-551 in the C-terminal tail were disordered.

The design and optimization of a series of 2-(pyridin-2-yl)-1H-benzimidazole compounds as allosteric glucokinase activators.

The optimization of a series of benzimidazole glucokinase activators is described. We identified a novel and potent achiral benzimidazole derivative as an allosteric GK activator. This activator was designed and synthesized via removal of the chiral center of the lead compound, 6-(N-acylpyrrolidin-2-yl)benzimidazole.

Discovery and structure-activity relationships of a novel class of quinazoline glucokinase activators.

We describe design, syntheses and structure-activity relationships of a novel class of 4,6-disubstituted quinazoline glucokinase activators. Prototype quinazoline leads (4 and 5) were designed based on the X-ray analyses of the previous 2-aminobenzamide lead classes. Modifications of the quinazoline leads led to the identification of a potent GK activator (21d).

Discovery of novel 3,6-disubstituted 2-pyridinecarboxamide derivatives as GK activators.

A novel class of 3,6-disubstituted 2-pyridinecarboxamide derivatives was designed based on X-ray analysis of the 2-aminobenzamide lead class. Subsequent chemical modification led to the discovery of potent GK activators which eliminate potential toxicity concerns associated with an aniline group of the lead structure. Compound 7 demonstrated glucose lowering effect in a rat OGTT model.

Discovery of potent and orally active 3-alkoxy-5-phenoxy-N-thiazolyl benzamides as novel allosteric glucokinase activators.

Identification and synthesis of novel 3-alkoxy-5-phenoxy-N-thiazolyl benzamides as glucokinase activators are described. Removal of an aniline structure of the prototype lead (2a) and incorporation of an alkoxy or phenoxy substituent led to the identification of 3-Isopropoxy-5-[4-(methylsulfonyl)phenoxy]-N-(4-methyl-1,3-thiazol-2-yl)benzamide (27e) as a novel, potent, and orally bioavailable GK activator. Rat oral glucose tolerance test indicated that 27e exhibited a glucose-lowering effect after 10 mg/kg oral administration.

Identification of novel and potent 2-amino benzamide derivatives as allosteric glucokinase activators.

The identification and structure-activity-relationships (SARs) of novel 2-amino benzamide glucokinase activators are described. Compounds in this series were developed to be potent GK activators, and their binding mode to the GK protein was determined by crystal structure analysis. In vivo pharmacokinetic and acute in vivo efficacy studies of compound 18 are also described.

Structural basis of nonnatural amino acid recognition by an engineered aminoacyl-tRNA synthetase for genetic code expansion.

The genetic code in a eukaryotic system has been expanded by the engineering of Escherichia coli tyrosyl-tRNA synthetase (TyrRS) with the Y37V and Q195C mutations (37V195C), which specifically recognize 3-iodo-L-tyrosine rather than L-tyrosine. In the present study, we determined the 3-iodo-L-tyrosine- and L-tyrosine-bound structures of the 37V195C mutant of the E. coli TyrRS catalytic domain at 2.

Structural snapshots of the KMSKS loop rearrangement for amino acid activation by bacterial tyrosyl-tRNA synthetase.

Tyrosyl-tRNA synthetase (TyrRS) has been studied extensively by mutational and structural analyses to elucidate its catalytic mechanism. TyrRS has the HIGH and KMSKS motifs that catalyze the amino acid activation with ATP. In the present study, the crystal structures of the Escherichia coli TyrRS catalytic domain, in complexes with l-tyrosine and a l-tyrosyladenylate analogue, Tyr-AMS, were solved at 2.

Structural basis for allosteric regulation of the monomeric allosteric enzyme human glucokinase.

Glucokinase is a monomeric enzyme that displays a low affinity for glucose and a sigmoidal saturation curve for its substrate, two properties that are important for its playing the role of a glucose sensor in pancreas and liver. The molecular basis for these two properties is not well understood. Herein we report the crystal structures of glucokinase in its active and inactive forms, which demonstrate that global conformational change, including domain reorganization, is induced by glucose binding.