Pseudoirreversible inhibition elicits persistent efficacy of a sphingosine 1-phosphate receptor 1 antagonist.

Sphingosine 1-phosphate receptor 1 (S1PR1), a G protein-coupled receptor, is required for lymphocyte trafficking, and is a promising therapeutic target in inflammatory diseases. Here, we synthesize a competitive S1PR1 antagonist, KSI-6666, that effectively suppresses pathogenic inflammation. Metadynamics simulations suggest that the interaction of KSI-6666 with a methionine residue Met124 in the ligand-binding pocket of S1PR1 may inhibit the dissociation of KSI-6666 from S1PR1.

Design, synthesis, and structure-activity relationships of a series of 4-benzyl-5-isopropyl-1H-pyrazol-3-yl β-D-glycopyranosides substituted with novel hydrophilic groups as highly potent inhibitors of sodium glucose co-transporter 1 (SGLT1).

Sodium glucose co-transporter 1 (SGLT1) plays a dominant role in the absorption of glucose in the gut and is considered a promising target in the development of therapeutic options for postprandial hyperglycemia. Previously, we reported potent and selective SGLT1 inhibitors 1 and 2 showing efficacy in oral carbohydrate tolerance tests in diabetic rat models. In a pharmacokinetic (PK) study of 2, excessive systemic exposure to metabolites of 2 was observed, presumably due to the high permeability of its aglycone (2a).

Structure-activity relationship studies of 4-benzyl-1H-pyrazol-3-yl β-d-glucopyranoside derivatives as potent and selective sodium glucose co-transporter 1 (SGLT1) inhibitors with therapeutic activity on postprandial hyperglycemia.

Sodium glucose co-transporter 1 (SGLT1) plays a dominant role in the absorption of glucose in the gut and is considered a promising target in the development of treatments for postprandial hyperglycemia. A series of 4-benzyl-1H-pyrazol-3-yl β-d-glucopyranoside derivatives have been synthesized, and its inhibitory activity toward SGLTs has been evaluated. By altering the substitution groups at the 5-position of the pyrazole ring, and every position of the phenyl ring, we studied the structure-activity relationship (SAR) profiles and identified a series of potent and selective SGLT1 inhibitors.

Long-term study of dental implants placed into alveolar cleft sites.

Objective: To evaluate the long-term prognosis of dental implants placed into cleft sites after bone grafting in a relatively large number of cases in order to clarify the usefulness of the modality.

Patients: Forty-seven patients with unilateral (dental, n=32) or bilateral (n=15) clefts of the alveolar process were included in this study.

Interventions: A total of 71 implants, including smooth- or rough-surface titanium, and hydroxyapatite (HA)-coated implants, were placed after bone grafting from the anterior iliac crest and/or mandible.

Alveolar bone graft for patients with cleft lip/palate using bone particles and titanium mesh: A quantitative study.

Purpose: This study evaluated the bone volume, height, and width that can be obtained in alveolar ridge augmentation using titanium mesh and autogenous bone particles in patients with cleft lip/palate.

Patients And Methods: Subjects were 15 patients with cleft lip/palate requiring tertiary bone graft for implant therapy. Computed tomography (CT) scans were taken before removing the mesh, from 1 to 21 months after bone grafting.

Effect of intermittent parathyroid hormone (1-34) treatment on the bone response after placement of titanium implants into the tibia of ovariectomized rats.

Purpose: This study investigated the effect of parathyroid hormone (1-34) [PTH(1-34)] on bone reactions after tibial placement of titanium screw implants into ovariectomized rats.

Materials And Methods: Twelve-week-old female Wistar rats were divided into 3 groups of 24. The first group (Sham group) was sham-operated; the second group (OVX group) was ovariectomized only; and the third group (PTH group) was subcutaneously administered 30 microg/kg PTH in the dorsal region 3 days per week starting the fourth week after ovariectomy until the end of the experiment.

Effects of bisphosphonate on bone reaction after placement of titanium implants in tibiae of ovariectomized rats.

Purpose: This study was undertaken to investigate the action of bisphosphonate on bone reactions after the placement of titanium screw implants into the tibiae of ovariectomized rats.

Materials And Methods: Twelve-week-old female Wistar rats were divided into 4 groups of 18 animals each. The first group (Sham) was sham-operated, the second group (OVX) was ovariectomized only, the third group (Estrogen) was ovariectomized and received continuous estrogen with a 17beta-estradiol pellet, and the fourth group (YM-175) was ovariectomized and received bisphosphonate at a dose of 10 microg/kg of body weight.

An anatomical study of vascularized iliac bone grafts for dental implantation.

Purpose: The purpose of this study was to clarify the anatomical features of vascularized iliac bone grafts used for mandibular reconstruction and dental implantation.

Material And Method: Twenty-six cadavers were dissected to examine vessels and areas of iliac bone that could be used as pedicles and grafts. The length and diameter of vessels of the vascular pedicle were determined, and the length and depths of the iliac bone were measured with respect to points determined by the relative dimensions of the bone.

Relationship of the mandibular canal to the lateral cortex of the mandibular ramus as a factor in the development of neurosensory disturbance after bilateral sagittal split osteotomy.

Purpose: This study evaluated the location of the mandibular canal in the ramus of the mandible before bilateral sagittal split ramus osteotomy and examined its relationship with postoperative neurosensory disturbance.

Patients And Methods: The subjects consisted of 20 patients undergoing bilateral sagittal split ramus osteotomy. Before surgery, the region from a plane containing the lowest point of the mandibular foramen to 22 mm below it was observed on transaxial computed tomograms acquired with a slice thickness of 2 mm and a slice interval of 2 mm.

Clinicoanatomic study on the craniofacial bones used for cranio- and maxillofacial implants.

Purpose: To clarify basic clinico-anatomic factors associated with cranio-maxillofacial rehabilitation using implants.

Materials And Methods: Morphometrically evaluated were items such as the length and width of bone and the thickness of cortical bone at important sites for implant placement into cranial and maxillofacial bones in 30 cadavers at autopsy.

Results: At sites corresponding to potential placement sites for implants as the fixation source for ocular epitheses, the mean length of bone was 7.