Discovery of GCC5694A: A potent and selective sodium glucose co-transporter 2 inhibitor for the treatment of type 2 diabetes.

Sodium-dependent glucose co-transporter 2 (SGLT2) has emerged as a promising drug target for the treatment of type 2 diabetes, and recently, several SGLT2 inhibitors have been approved for clinical use. A series of molecules with a C-aryl glucoside scaffold was designed and synthesized for biological evaluation. Among the molecules tested, a dihydrobenzofuran-containing analog, 14g (GCC5694A), exhibited excellentin vitro activity against SGLT2 (IC = 0.

Oncologic comparison between nonradical management and total mesorectal excision in good responders after chemoradiotherapy in patients with mid-to-low rectal cancer.

Purpose: This study was performed to compare the oncologic outcomes between nonradical management and total mesorectal excision in good responders after chemoradiotherapy.

Methods: We analyzed 75 patients, who underwent 14 watch-and-wait, 30 local excision, and 31 total mesorectal excision, in ycT0-1N0M0 based on magnetic resonance imaging after chemoradiotherapy for advanced mid-to-low rectal cancer in 3 referral hospitals. The nonradical management group underwent surveillance with additional sigmoidoscopy and rectal magnetic resonance imaging every 3-6 months within the first 2 years.

Small Bowel Perforation Associated With Gastrointestinal Graft-Versus-Host Disease and Cytomegalovirus Enteritis in a Patient With Leukemia: A Case Report With Literature Review.

Gastrointestinal graft-versus-host disease (GVHD) is a common complication after hematopoietic stem cell transplantation. Concomitant cytomegalovirus (CMV) enteritis worsens the prognosis of this condition. We report a case of small bowel perforation associated with gastrointestinal GVHD and CMV enteritis in a patient with leukemia who was successfully treated surgically.

Oncologic Risk of Rectal Preservation Against Medical Advice After Chemoradiotherapy for Rectal Cancer: A Multicenter Comparative Cross-Sectional Study with Rectal Preservation as Supported by Surgeon.

Background: Rectal preservation against medical advice after neoadjuvant chemoradiotherapy for rectal cancer may increase oncologic uncertainty. This study aimed to compare the oncologic outcomes of patients undergoing rectal preservation as intended by the surgeon, and the outcomes of patients refusing rectal resection against medical advice.

Methods: The study population consisted of patients in whom the rectum was preserved after neoadjuvant chemoradiotherapy for clinical stage I-III mid or low rectal cancer between May 2003 and August 2017 (n = 2883); these patients were divided into those in whom rectal preservation was intended by their surgeon (intended rectal preservation, group A, n = 41) and those in whom the rectum was not resected against medical advice (unintended rectal preservation, group B, n = 101), defined as non-operative management or local excision.

Differences in prognostic relevance of rectal magnetic resonance imaging findings before and after neoadjuvant chemoradiotherapy.

This retrospective study was designed to compare prognostic relevance of magnetic resonance imaging (MRI) findings before and after neoadjuvant chemoradiotherapy (CRT). From 2002 to 2010, 399 patients who underwent surgery after CRT for rectal cancer (≥T3) and had adequate pre-CRT (mr) and post-CRT (ymr) MRI findings were examined. Factors examined included tumour (T), lymph node (N), mesorectal fascia (MRF), extramural venous invasion (EMVI), and tumour regression grade (TRG).

Does Tumor Size Influence the Diagnostic Accuracy of Ultrasound-Guided Fine-Needle Aspiration Cytology for Thyroid Nodules?

. Fine-needle aspiration cytology (FNAC) is diagnostic standard for thyroid nodules. However, the influence of size on FNAC accuracy remains unclear especially in too small or too large thyroid nodules.

Novel thiophenyl C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents.

Novel thiophene C-aryl glucoside SGLT2 inhibitors were designed and synthesized. Two different types of thiophene derivatives were readily prepared. Among the compounds tested, ethylphenyl at the distal ring 71p showed the best in vitro inhibitory activity in this series to date (IC(50)=4.

Synthesis and SAR of Thiazolylmethylphenyl Glucoside as Novel C-Aryl Glucoside SGLT2 Inhibitors.

Novel C-aryl glucoside SGLT2 inhibitors containing the thiazole motif were designed and synthesized for biological evaluation. Among the compounds assayed, thiazole containing furanyl moiety 14v and thiophenyl moiety 14y demonstrated the best in vitro inhibitory activity against SGLT2 in this series to date (IC50 = 0.720 nM for 14v and IC50 = 0.

Discovery of 2-(4-((1H-1,2,4-triazol-1-yl)methyl)-5-(4-bromophenyl)-1-(2-chlorophenyl)-1H-pyrazol-3-yl)-5-tert-butyl-1,3,4-thiadiazole (GCC2680) as a potent, selective and orally efficacious cannabinoid-1 receptor antagonist.

Structure-activity relationship studies in a series of diarylpyrazolyl thiadiazoles identified cannabinoid-1 receptor antagonists with excellent potency and selectivity. Based on its exceptional in vivo efficacy in animal models and its favorable pharmacokinetic and toxicological profiles, 2-(4-((1H-1,2,4-triazol-1-yl)methyl)-5-(4-bromophenyl)-1-(2-chlorophenyl)-1H-pyrazol-3-yl)-5-tert-butyl-1,3,4-thiadiazole (GCC2680) was selected as a preclinical candidate for the treatment of obesity.

Synthesis of pyridazine and thiazole analogs as SGLT2 inhibitors.

With anticipation of the improvement in biological aspects in our SGLT2 program, novel pyridazinyl and thiazolyl analogs were designed and efficiently synthesized. The installation of the pyridazine ring at the anomeric carbon of d-glucopyranose was carried out in a stereoselective fashion. On the other hand, a series of thiazolyl analogs was also synthesized through a coupling reaction between perbenzyl gluconolactone 9 and 2-lithiothiazole.

Novel C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents: Pyridazinylmethylphenyl glucoside congeners.

Novel C-aryl glucoside SGLT2 inhibitors containing pyridazine motif were designed and synthesized for biological evaluation. Among the compounds tested, pyridazine containing methylthio moiety 22l or thiadiazole ring 22ah showed the best in vitro inhibitory activities in this series (IC(50)=13.4, 11.

Arylpiperazine-containing pyrrole 3-carboxamide derivatives targeting serotonin 5-HT(2A), 5-HT(2C), and the serotonin transporter as a potential antidepressant.

Arylpiperzine-containing pyrrole 3-carboxamide derivatives were synthesized and evaluated as novel antidepressant compounds. The various analogues were efficiently prepared and bio-assayed for binding to 5-HT(2A), 5-HT(2C) receptor, and 5-HT transporter. Based on their in vitro and in vivo activities as well as selectivity over other neurotransmitter receptors and PK profiles, 33 and 34 were identified as lead compounds.

New trends in medicinal chemistry approaches to antiobesity therapy.

The prevalences of overweightedness and obesity are increasing globally at frightening rates, driven by social and economic changes. Furthermore, obesity is associated with the pathogeneses of major diseases, particularly diabetes and cardiovascular diseases. However, no satisfactorily safe, effective obesity drugs are commercially available at the present time.

Methylsulfonylpyrazolyl oxadiazoles and thiadiazoles as potent, orally bioavailable cannabinoid-1 receptor antagonists for the treatment of obesity.

Background: Since the cannabinoid receptor 1 (CB1) antagonist SR141716 (rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity.

Discussion: In the present study, biarylpyrazole analogues based on a sulfur-containing pyrazole core coupled with 1,3,4-oxadiazole and 1,3,4-thiadiazole were synthesized and assayed for rat CB1 receptor binding affinity.

Results: The structure-activity relationship studies to optimize pyrazole substituents as well as 1,3,4-oxadiazole or 1,3,4-thiadiazole rings led to four novel CB1 antagonists with IC(50) values of approximately 1 nM for the rat CB1 receptor binding.

Synthesis and structure-activity relationship of novel diarylpyrazole imide analogues as CB1 cannabinoid receptor ligands.

A myriad of research groups have been engaged in searching for novel CB1 receptor antagonists, since SR141716A (rimonabant), a CB1 receptor antagonist, was discovered for an obesity treatment. In this research, extended series, based on the 1,5-diarylpyrazole template of rimonabant, was synthesized and tested for CB1 receptor binding affinity. In the present study, N-piperidinylcarboxamide group of rimonabant was replaced with the corresponding sulfonamide, imide, N-methyl imide and methylenediamide, respectively.

Oxadiazole-diarylpyrazole 4-carboxamides as cannabinoid CB1 receptor ligands.

Cannabinoid CB-1 receptors have been the focus of extensive studies since the first clinical results of rimonabant (SR141716) for the treatment of obesity and obesity-related metabolic disorders were reported in 2001. To further evaluate the properties of CB receptors, we have designed and efficiently prepared a series of oxadiazole-diarylpyrazole 4-carboxamides. Six of the new compounds which displayed high in vitro CB1 binding affinities were assayed for binding to CB2 receptor.

Biarylpyrazolyl oxadiazole as potent, selective, orally bioavailable cannabinoid-1 receptor antagonists for the treatment of obesity.

Since the CB1 cannabinoid receptor antagonist 1 (SR141716, rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity. In the present study, biarylpyrazole analogues based on a pyrazole core coupled with 1,3,4-oxadiazole were synthesized and tested for CB1 receptor binding affinity. Thorough SAR studies to optimize pyrazole substituents as well as 1,3,4-oxadiazole ring led to several novel CB1 antagonists with IC(50) approximately 1 nM for the CB1 receptor binding.

Design, synthesis and biological evaluation of piperazine analogues as CB1 cannabinoid receptor ligands.

After the CB1 receptor antagonist SR141716 (rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity. Several series of urea, carbamate, amide, sulfonamide and oxalamide derivatives based on 1-benzhydrylpiperazine scaffold were synthesized and tested for CB1 receptor binding affinity. The SAR studies to optimize the CB1 binding affinity led to the potent urea derivatives.

Identification of class 2 1-deoxy-D-xylulose 5-phosphate synthase and 1-deoxy-D-xylulose 5-phosphate reductoisomerase genes from Ginkgo biloba and their transcription in embryo culture with respect to ginkgolide biosynthesis.

Diterpenoid ginkgolides having potent platelet-activating factor antagonist activity are major active ingredients of ginkgo extract. Class 2-type 1-deoxy-D-xylulose 5-phosphate synthase (GbDXS2) and 1-deoxy-D-xylulose 5-phosphate reductoisomerase (GbDXR), the first two enzymes in 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway, operating in the earlier step of ginkgolide biosynthesis, were cloned from embryonic roots of Ginkgo biloba through a homology-based polymerase chain reaction for role assessment of the enzymes. Plasmids harboring each gene rescued the respective knockout E.