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1.
Bioorg Med Chem Lett ; 56: 128466, 2022 01 15.
Article in English | MEDLINE | ID: mdl-34813882

ABSTRACT

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 (IC50 = 0.460 nM), good selectivity for SGLT1, and good metabolic stability. Data from further evaluation of the compound in animal models showed that this molecule is a promising candidate for development as an anti-diabetic agent.


Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Drug Discovery , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Sodium-Glucose Transporter 2/metabolism , Administration, Oral , Animals , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 2/chemically induced , Diabetes Mellitus, Type 2/metabolism , Dose-Response Relationship, Drug , Humans , Molecular Structure , Rats , Rats, Sprague-Dawley , Sodium-Glucose Transporter 2 Inhibitors/administration & dosage , Sodium-Glucose Transporter 2 Inhibitors/chemistry , Structure-Activity Relationship
2.
Ann Surg Treat Res ; 101(2): 93-101, 2021 Aug.
Article in English | MEDLINE | ID: mdl-34386458

ABSTRACT

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. RESULTS: Nonradical management group had more low-lying tumors (P < 0.001) and less lymph node metastasis based on magnetic resonance imaging (P = 0.004). However, cT stage, ycT, and ycN stage were not different between the 2 groups. With a median follow-up period of 64.7 months, the 5-year locoregional failure rate was higher in the nonradical management group than in the total mesorectal excision group (16.7% vs. 0%, P = 0.013). However, the 5-year overall survival and disease-free survival rates of the nonradical management and total mesorectal excision groups were not different (95.2% vs. 93.5%, P = 0.467; 76.4% vs. 83.6%, P = 0.665; respectively). CONCLUSION: This study shows that nonradical management for ycT0-1N0 mid-to-low rectal cancer may be an alternative treatment to total mesorectal excision under proper surveillance and management for oncologic events.

3.
Ann Coloproctol ; 36(4): 281-284, 2020 Aug.
Article in English | MEDLINE | ID: mdl-32919438

ABSTRACT

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. A 39-year-old man presented with intestinal perforation necessitating emergency surgical intervention. He was diagnosed with T-cell acute lymphoblastic leukemia and developed severe gastrointestinal GVHD and CMV enteritis after hematopoietic stem cell transplantation. His terminal ileum showed a perforation with diffuse wall thinning, and petechiae were observed over long segments of the distal ileum and the proximal colon. Small bowel segmental resection and a subtotal colectomy with a double-barreled ileocolostomy were performed. The patient recovered uneventfully after the operation. Based on reports described in the literature, surgery plays a minor role in the management of gastrointestinal GVHD; however, timely surgical intervention could be effective in selected patients.

4.
World J Surg ; 43(12): 3216-3223, 2019 12.
Article in English | MEDLINE | ID: mdl-31410512

ABSTRACT

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. RESULTS: The tumor distance, age, and performance status of patients were not significantly different between the groups, while the clinical T stage before chemoradiotherapy was lower in group A than in group B (P < 0.001). During the median follow-up period of 34 months (interquartile range 18.0-72.0 months), the 3-year overall survival in group B (59.7%) was worse than that in group A (90.1%; P < 0.001), and 80.2% of group B patients had residual or unknown disease status. CONCLUSIONS: This study showed that unintended rectal preservation increases oncologic risk after neoadjuvant chemoradiotherapy for rectal cancer regardless of short-term follow-up. Therefore, these findings could be shared with rectal cancer patients who choose to ignore medical advice after chemoradiotherapy to preserve their rectum.


Subject(s)
Chemoradiotherapy , Rectal Neoplasms/therapy , Rectum/surgery , Aged , Cross-Sectional Studies , Equipment and Supplies , Female , Humans , Male , Middle Aged , Neoplasm Staging , Rectal Neoplasms/pathology , Retrospective Studies
5.
Sci Rep ; 9(1): 10059, 2019 07 11.
Article in English | MEDLINE | ID: mdl-31296960

ABSTRACT

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). Two Cox proportional hazard models were created using mr and ymr findings separately for overall survival (OS), disease-free survival (DFS), and local recurrence rate (LRR). Among mr findings, only mrEMVI was a significant prognostic factor for OS and DFS. Among ymr findings, ymrN, ymrMRF, and ymrEMVI were significant prognostic factors for OS and DFS, whereas ymrMRF and ymrEMVI were significant prognostic factors for LRR. C-indices tended to be higher for ymr findings than for mr findings (OS, 0.682 vs. 0.635; DFS, 0.660 vs. 0.631; LRR, 0.701 vs. 0.617). Survival outcomes of patients having all ymr risk factors were significantly poor (5-year OS, 52.4%; 5-year DFS, 38.1%; 5-year LRR, 27.7%). ymr findings showed better prognostic significance than mr findings. Among ymr findings, ymrN, ymrMRF, and ymrEMVI were independent prognostic factors for oncologic outcomes.


Subject(s)
Lymph Nodes/diagnostic imaging , Magnetic Resonance Imaging/methods , Rectal Neoplasms/diagnostic imaging , Rectum/diagnostic imaging , Aged , Chemoradiotherapy , Female , Follow-Up Studies , Humans , Male , Neoadjuvant Therapy , Neovascularization, Physiologic , Prognosis , Rectal Neoplasms/drug therapy , Rectal Neoplasms/mortality , Retrospective Studies , Survival Analysis
6.
Neural Regen Res ; 8(10): 922-9, 2013 Apr 05.
Article in English | MEDLINE | ID: mdl-25206384

ABSTRACT

The hippocampus is a brain region responsible for learning and memory functions. The purpose of this study was to investigate the effects of low-intensity exercise and bright light exposure on neurogenesis and brain-derived neurotrophic factor expression in adult rat hippocampus. Male Sprague-Dawley rats were randomly assigned to control, exercise, light, or exercise + light groups (n = 9 per group). The rats in the exercise group were subjected to treadmill exercise (5 days per week, 30 minutes per day, over a 4-week period), the light group rats were irradiated (5 days per week, 30 minutes per day, 10 000 lx, over a 4-week period), the exercise + light group rats were subjected to treadmill exercise in combination with bright light exposure, and the control group rats remained sedentary over a 4-week period. Compared with the control group, there was a significant increase in neurogenesis in the hippocampal dentate gyrus of rats in the exercise, light, and exercise + light groups. Moreover, the expression level of brain-derived neurotrophic factor in the rat hippocampal dentate gyrus was significantly higher in the exercise group and light group than that in the control group. Interestingly, there was no significant difference in brain-derived neurotrophic factor expression between the control group and exercise + light group. These results indicate that low-intensity treadmill exercise (first 5 minutes at a speed of 2 m/min, second 5 minutes at a speed of 5 m/min, and the last 20 minutes at a speed of 8 m/min) or bright-light exposure therapy induces positive biochemical changes in the brain. In view of these findings, we propose that moderate exercise or exposure to sunlight during childhood can be beneficial for neural development.

7.
Bioorg Med Chem ; 19(19): 5813-32, 2011 Oct 01.
Article in English | MEDLINE | ID: mdl-21906953

ABSTRACT

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)=4.47 nM) against SGLT2.


Subject(s)
Glucosides/chemistry , Hypoglycemic Agents/chemistry , Sodium-Glucose Transporter 2 Inhibitors , Thiophenes/chemistry , Benzhydryl Compounds , Glucosides/chemical synthesis , Glucosides/pharmacology , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacology , Sodium-Glucose Transporter 2/metabolism , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/pharmacology
8.
ACS Med Chem Lett ; 2(2): 182-7, 2011 Feb 10.
Article in English | MEDLINE | ID: mdl-24900297

ABSTRACT

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 = 0.772 nM for 14y). Both of these compounds have been further evaluated on a urinary glucose excretion test and the urine volumes excreted.

9.
Bioorg Med Chem ; 18(17): 6377-88, 2010 Sep 01.
Article in English | MEDLINE | ID: mdl-20673729

ABSTRACT

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.


Subject(s)
Receptor, Cannabinoid, CB1/antagonists & inhibitors , Thiadiazoles/pharmacology , Animals , CHO Cells , Cricetinae , Cricetulus , Humans , Male , Mice , Mice, Inbred C57BL , Obesity/drug therapy , Rats , Rats, Sprague-Dawley , Receptor, Cannabinoid, CB1/chemistry , Structure-Activity Relationship , Thiadiazoles/chemical synthesis , Thiadiazoles/chemistry , Thiadiazoles/pharmacokinetics
10.
Bioorg Med Chem ; 18(16): 6069-79, 2010 Aug 15.
Article in English | MEDLINE | ID: mdl-20637636

ABSTRACT

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. Biological activities of the compounds thus prepared were evaluated by the in vitro SGLT2 inhibition assay. Considering assay results, the novel benzylpyridazinyl and benzylthiazolyl analogs, disclosed in this article, could be a quick reference to prospective SGLT2 inhibitors useful for pharmacotherapy.


Subject(s)
Pyridazines/chemistry , Pyridazines/pharmacology , Sodium-Glucose Transporter 2 Inhibitors , Sodium-Glucose Transporter 2/metabolism , Thiazoles/chemistry , Thiazoles/pharmacology , Humans , Pyridazines/chemical synthesis , Structure-Activity Relationship , Thiazoles/chemical synthesis
11.
Bioorg Med Chem Lett ; 20(11): 3420-5, 2010 Jun 01.
Article in English | MEDLINE | ID: mdl-20434909

ABSTRACT

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, 11.4nM, respectively) against SGLT2 to date. Subsequently, compound 22l exhibited reasonable urinary glucose excretion and glucosuria in normal SD rats, thereby demonstrating that this pyridazine series possesses both in vitro SGLT2 inhibition and in vivo efficacy, albeit to a lower degree.


Subject(s)
Glucosides/pharmacology , Hypoglycemic Agents/pharmacology , Sodium-Glucose Transporter 2 Inhibitors , Animals , Rats , Rats, Sprague-Dawley , Sodium-Glucose Transporter 2
12.
Bioorg Med Chem Lett ; 20(5): 1705-11, 2010 Mar 01.
Article in English | MEDLINE | ID: mdl-20149649

ABSTRACT

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. Consequently, this pyrrole series of compounds appears to be promising enough to warrant further investigation.


Subject(s)
Amides/chemistry , Antidepressive Agents/chemistry , Piperazines/chemistry , Pyrroles/chemistry , Selective Serotonin Reuptake Inhibitors/chemistry , Serotonin 5-HT2 Receptor Antagonists , Serotonin Plasma Membrane Transport Proteins/chemistry , Administration, Oral , Amides/chemical synthesis , Amides/pharmacokinetics , Animals , Antidepressive Agents/chemical synthesis , Antidepressive Agents/pharmacokinetics , Injections, Intravenous , Mice , Piperazine , Piperazines/chemical synthesis , Piperazines/pharmacokinetics , Pyrroles/chemical synthesis , Pyrroles/pharmacokinetics , Rats , Receptor, Serotonin, 5-HT2A/metabolism , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Structure-Activity Relationship
13.
Curr Top Med Chem ; 9(6): 564-96, 2009.
Article in English | MEDLINE | ID: mdl-19689366

ABSTRACT

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. Only two drugs have been approved in the United States for the long-term treatment of obesity, sibutramine and orlistat. However, these drugs are minimally effective and have significant side effects, which are likely inhibit their use. Therefore, there is a huge opportunity to make a significant impact on the lives of obese people through the discovery and development of additional pharmacotherapeutic options. In this review article, the authors focus on selected trends in medicinal chemistry and the approaches used to develop drugs for treating obesity.


Subject(s)
Anti-Obesity Agents/chemistry , Chemistry, Pharmaceutical/trends , Obesity/drug therapy , Animals , Anti-Obesity Agents/pharmacology , Anti-Obesity Agents/therapeutic use , Clinical Trials as Topic , Drug Evaluation, Preclinical , Humans , Molecular Structure
14.
Bioorg Med Chem Lett ; 19(7): 1899-902, 2009 Apr 01.
Article in English | MEDLINE | ID: mdl-19269817

ABSTRACT

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. Noticeably, 5-(4-bromophenyl)-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-(2,4-dichlorophenyl)-N-phenyl-1H-pyrazole-4-carboxamide (12q) and 5-(4-bromophenyl)-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-(2,4-dichlorophenyl)-N-(pyridin-2-yl)-1H-pyrazole-4-carboxamide (12r) demonstrated good binding affinity and decent selectivity for CB1 receptor (IC(50) = 1.35 nM, CB2/CB1 = 286 for 12q; IC(50) = 1.46 nM, CB2/CB1 = 256 for 12r).


Subject(s)
Anti-Obesity Agents/chemical synthesis , Oxadiazoles/chemical synthesis , Pyrazoles/chemical synthesis , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Animals , Anti-Obesity Agents/chemistry , Anti-Obesity Agents/pharmacology , CHO Cells , Cricetinae , Cricetulus , Inhibitory Concentration 50 , Ligands , Obesity/drug therapy , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Receptor, Cannabinoid, CB1/metabolism , Structure-Activity Relationship , Transfection
15.
Bioorg Med Chem ; 17(8): 3080-92, 2009 Apr 15.
Article in English | MEDLINE | ID: mdl-19328001

ABSTRACT

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. The SAR studies to optimize the CB1 binding affinity led to the potent imide derivatives. The in vivo efficacy test of a derivative (16f) gave a promising result for this novel scaffold. In order to explore physicochemical properties (hydrophobic, steric and electronic) of the representative imide derivatives responsible for their CB1 receptor binding affinity, quantitative structure activity relationship (QSAR) studies were performed. Hansch QSAR models, which were moderate in the explanation for SAR, were generated with hydrophobic, steric and electronic properties of substituents. Especially, the Taft Es-based parabolic model was obtained with the best correlation result (r(2)=0.846).


Subject(s)
Piperidines/chemistry , Piperidines/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Animals , Drug Design , Imides/chemical synthesis , Imides/chemistry , Imides/pharmacology , Ligands , Male , Mice , Mice, Inbred C57BL , Piperidines/chemical synthesis , Protein Binding , Pyrazoles/chemical synthesis , Quantitative Structure-Activity Relationship , Rats , Rats, Sprague-Dawley , Receptor, Cannabinoid, CB1/chemistry , Rimonabant
16.
Future Med Chem ; 1(5): 947-67, 2009 Aug.
Article in English | MEDLINE | ID: mdl-21426091

ABSTRACT

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. Among these derivatives, we identified trifluoromethylcyclobutyl analogues 19e and 19l as promising precandidates for the development as anti-obesity agents.


Subject(s)
Anti-Obesity Agents/chemistry , Obesity/drug therapy , Oxadiazoles/chemistry , Pyrazoles/chemistry , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Thiadiazoles/chemistry , Administration, Oral , Animals , Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/therapeutic use , Binding Sites , Biological Availability , Computer Simulation , Humans , Mice , Oxadiazoles/pharmacokinetics , Oxadiazoles/therapeutic use , Pyrazoles/pharmacokinetics , Pyrazoles/therapeutic use , Rats , Receptor, Cannabinoid, CB1/metabolism , Structure-Activity Relationship , Thiadiazoles/pharmacokinetics , Thiadiazoles/therapeutic use
17.
J Med Chem ; 51(22): 7216-33, 2008 Nov 27.
Article in English | MEDLINE | ID: mdl-18954042

ABSTRACT

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. Among these analogues, we identified 2-(4-((1H-1,2,4-triazol-1-yl)methyl)-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)-5-(1-(trifluoromethyl)cyclopropyl)-1,3,4-oxadiazole 43c as a promising precandidate for the development as an antiobesity agent.


Subject(s)
Obesity/drug therapy , Oxadiazoles/pharmacology , Pyrazoles/pharmacology , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Computer Simulation , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Male , Mice , Mice, Inbred C57BL , Models, Chemical , Models, Molecular , Molecular Structure , Oxadiazoles/chemical synthesis , Oxadiazoles/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Rats , Rats, Sprague-Dawley , Receptor, Cannabinoid, CB2/antagonists & inhibitors , Stereoisomerism , Structure-Activity Relationship
18.
Bioorg Med Chem ; 16(7): 4035-51, 2008 Apr 01.
Article in English | MEDLINE | ID: mdl-18243711

ABSTRACT

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. After the additional SAR studies to optimize the substituents of diphenyl rings, the combination of 2-chlorophenyl and 4-chlorophenyl turned out to be the most potent scaffold. The CB2 binding affinity assay as well as functional assay was also conducted on these compounds. Herein we wish to introduce several novel CB1 antagonists with IC(50) values less than 100 nM for the CB1 receptor binding.


Subject(s)
Drug Design , Piperazines/chemical synthesis , Piperazines/pharmacology , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Receptor, Cannabinoid, CB1/metabolism , Animals , Humans , Ligands , Male , Molecular Structure , Piperazine , Piperazines/chemistry , Protein Binding , Rats , Rats, Sprague-Dawley , Receptor, Cannabinoid, CB2/metabolism , Structure-Activity Relationship
19.
Planta Med ; 72(3): 234-40, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16534728

ABSTRACT

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. coli mutants. The levopimaradiene synthase gene (LPS), responsible for the first committed step in ginkgolide biosynthesis, and GbDXS2 were transcribed exclusively in embryonic root, suggesting a specific role of GbDXS2 in ginkgolide biosynthesis. GbDXR retained a higher transcription level in roots than in leaves, whereas class 1 DXS (GbDXS1) showed 30 to 50 % higher level in leaves. Ginkgolides and bilobalide were found both in leaves and roots from an earlier stage of the embryo culture. Exclusive transcription of ginkgolide biosynthesis-specific LPS and GbDXS2 in roots and the appearance of ginkgolides in leaves was consistent with translocation of the compounds from roots to leaves.


Subject(s)
Aldose-Ketose Isomerases/genetics , Ginkgo biloba/genetics , Ginkgolides/metabolism , Multienzyme Complexes/genetics , Oxidoreductases/genetics , Phytotherapy , Transferases/genetics , Aldose-Ketose Isomerases/chemistry , Aldose-Ketose Isomerases/metabolism , Amino Acid Sequence , Base Sequence , DNA Primers , DNA, Plant/chemistry , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Plant , Genes, Plant , Ginkgo biloba/enzymology , Ginkgo biloba/metabolism , Humans , Molecular Sequence Data , Multienzyme Complexes/chemistry , Multienzyme Complexes/metabolism , Oxidoreductases/chemistry , Oxidoreductases/metabolism , Phylogeny , Plant Leaves , Plant Roots , Plants, Genetically Modified , Reverse Transcriptase Polymerase Chain Reaction , Sequence Alignment , Tissue Culture Techniques , Transferases/chemistry , Transferases/metabolism
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