Design and synthesis of novel arylpiperazine derivatives containing the imidazole core targeting 5-HT(2A) receptor and 5-HT transporter.

Serotonin antagonist reuptake inhibitor (SARI) drugs that block both 5-HT(2) receptors and the serotonin transporters have been developed. The human 5-HT(2A/2C) receptor has been implicated in several neurological conditions, and potent selective 5-HT(2A/2C) ligands may have therapeutic potential for treatment of CNS diseases such as depression. An imidazole moiety usually provides good pharmacokinetic properties as a drug substance, and thus considerable efforts have been devoted to develop imidazole derivatives into drug candidates. The imidazole series of compounds was evaluated against 5-HT(2A/2C) and serotonin reuptake inhibition. A few of the compounds in the series showed promising IC(50) values and antidepressant-like effect in in vivo forced swimming test (FST). On the basis of these results, further lead optimization studies resulted in identifying promising compounds potentially for therapeutic use.

Glucosides with cyclic diarylpolynoid as novel C-aryl glucoside SGLT2 inhibitors.

Novel C-aryl glucoside SGLT2 inhibitors containing cyclic diarylpolynoid motif were designed and synthesized for biological evaluation. Alkylzinc bromides have been efficiently prepared by the direct insertion of zinc metal into alkyl bromides. The organozinc reagents underwent smooth Pd-catalyzed cross-coupling reactions. Subsequent ring closing metathesis using 2nd generation Grubbs catalyst successfully generated novel class of ansa-compounds. These glucosides with cyclic diarylpolynoids demonstrated moderate in vitro inhibitory activity against SGLT2 in this series to date (IC(50)=59.5-103 nM).

Arylpiperazine-containing pyrimidine 4-carboxamide derivatives targeting serotonin 5-HT(2A), 5-HT(2C), and the serotonin transporter as a potential antidepressant.

Pyrimidine usually has good pharmacokinetic properties as a drug substance and considerable efforts have been devoted to develop pyrimidine derivatives into drug candidates. Arylpiperazine-containing pyrimidine 4-carboxamide derivatives were synthesized and evaluated for binding to serotonin receptors and transporter. Pyrimidine derivatives showed good antidepressant activity in FST (forced swimming test) animal model and also displayed no appreciable inhibitory activity against hERG channel blocking assay. Herein SAR studies of pyrimidine derivatives targeting serotonin receptors and transporter will be disclosed.

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.

Further optimization of novel pyrrole 3-carboxamides for targeting serotonin 5-HT(2A), 5-HT(2C), and the serotonin transporter as a potential antidepressant.

In the continuing search for novel compounds targeting serotonin 5-HT(2A), 5-HT(2C), and serotonin transporter, new arylpiperazine-containing pyrrole 3-carboxamide derivatives were synthesized and evaluated. Based on the lead reported previously, structural modifications regarding N-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)-1,2-dimethyl-5-phenyl-1H-pyrrole-3-carboxamide 5, were accomplished for improvements in not only binding affinity against serotonin receptors and transporter, but also in hERG channel inhibition. Along the line, both the forced swimming tests and spontaneous locomotor activity tests were performed to distinguish between antidepressant activity and false positive results. As potential antidepressant agents, both 2,4-dimethyl-5-phenyl-1H-pyrrole-3-carboxamide and 5-tert-butyl-2-methyl-1H-pyrrole-3-carboxamide derivatives exhibited favorable in vitro and in vivo activities, warranting further investigation around these scaffolds.

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. 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.

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, 11.4nM, 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.

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

Pentacycle derivatives 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 pentacycle derivatives. Five of the new compounds which displayed high in vitro rCB1 binding affinities were assayed for binding to hCB2 receptor. Noticeably, 2-(5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-pyrazol-3-yl)-5-(1-(trifluoromethyl)cyclopropyl)-1,3,4-oxadiazole (16l) demonstrated good binding affinity and decent selectivity for rCB1 receptor (IC(50)=1.72 nM, hCB2/rCB1=142).

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. 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).

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. 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.

Tetrazole-biarylpyrazole derivatives as cannabinoid CB1 receptor antagonists.

Cannabinoid CB1 receptors have been the focus of extensive studies since the first clinical results of rimonabant (SR141716) for the treatment of obesity and related metabolic disorders were reported in 2001. To further evaluate the properties of CB receptors, we have designed a new series of tetrazole-biarylpyrazoles. The various analogues were efficiently prepared and bio-assayed for binding to cannabinoid CB1 receptor. Six of the new compounds which displayed high in vitro CB1 binding affinities were assayed for binding to CB2 receptor. Noticeably, cyclopentyl-tetrazole (9a) demonstrated good binding affinity and selectivity for CB1 receptor (IC(50)=11.6nM and CB2/CB1=366).

A case of ruptured tuboovarian abscess into the anterior abdominal wall / 대한산부인과학회지

Rupture of a tuboovarian abscess usually presents with sudden worsening of the patient's condition. Delays in surgical debridement and drainage increase the rate of associated mortality. A 39-year-old woman represents extraperitoneal spillage of abscess contents from rupture of a tuboovarian abscess into the anterior abdominal wall. She presented with gradually worsening abdominal pain over several months. She had fever, pelvic tenderness, an elevated white blood cell count and evidence of a tuboovarian abscess. Also she was found to have an abscess that had ruptured into the anterior left abdominal wall. After triple antibiotic therapy without a clinical improvement, she underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy and surgical debridement of the abdominal wall. Over the following several weeks, the patient required extensive wound care for wound drainage and skin flap.

Clinical study in children with cerebral palsy associated with or without epilepsy / 소아과

PURPOSE: To study the spectrum of epilepsy in children with cerebral palsy. METHODS: A total of 93 consecutive patients with cerebral palsy(CP) were retrospectively suited. Criteria for inclusion were a follow-up period of at least 2 years. The study examined the correlation between the incidence of epilepsy and seizure types in the different forms of CP. Other factors associated with epilepsy, such as age of first seizure, occurrence of abnormalities on brain imaging, and electroencephalogram were also analyzed. RESULTS: The overall prevalence of epilepsy in children with CP was 46.2 percent. The incidence of epilepsy was predominant in patients with mixed, diplegic, and quadriplegic palsies:55.5 percent, 51.6 percent, and 50.0 percent in frequency. The first seizure occurred during the first year of life in 48.8 percent of patients with epilepsy. Generalized tonic-clonic seizures were the most common seizure type(44.2 percent), predominant in diplegic patients(64.3 percent). On the other hand, infantile spasms and myoclonic seizures were the main cause of seizures among quadriplegic children(60 percent and 40 percent, respectively). The occurrence of epilepsy was more popular in the group with abnormal brain imagings; especially encephalomalacia and cortical atrophy. All children with epilepsy in this study showed abnormal electroencephalogram(EEG) findings: Generalized abnormalities were observed in 55.8 percent of children with epilepsy; more dominantly in quadriplegic children(80.0 percent); and 40 percent of children with diplegia showed focal abnormalities. CONCLUSION: Cerebral palsy is associated with a higher incidence of seizure disorders, which, in the majority, has its onset in the first year of life; brain imaging and EEG are most effective in spotting epilepsy in children with CP.

Histopathologic Diagnosis and Outcome of Renal Biopsied Pediatric Nephrotic Syndrome

PURPOSE: To determine the histological findings and treatment outcome in cases of childhood nephrotic syndrome which required renal biopsy. METHODS: We retrospectively reviewed the clinical, laboratory, pathologic findings and therapeutic outcomes of 169 nephrotic children who received a renal biopsy at the Department of Pediatrics, Kyunghee Medical University Hospital, Seoul from 1984 to 2004 over a period of 21 years. The renal biopsy was performed in nephrotic children who showed atypical features at presentation, or needed cytotoxic therapy because of frequent-relapsing, steroid-dependent, or steroid-resistant nephrotic syndrome(SRNS). RESULTS: Minimal change disease(MCD) was found in 52.1% of the patients, followed by diffuse mesangial proliferation(33.1%), focal segmental gomerulosclerosis(5.3%), membranoproliferative glomerulonephritis(2.4%), membranous nephropathy(2.4%), and IgA nephropathy(1.8 %). In MCD children, 14.8% had hematuria, 22.7% had hypertension, 5.7% showed decreased renal function, and no patient was found to have an abnormal complement level. Among patients diagnosed with diseases other than MCD, 43.2% had hematuria, 21.0% was found to be hypertensive, 7.4% of children showed decreased renal function and only 3(3.7%) had decreased complement level; the rates of hematuria and SRNS were found to be significantly higher than MCD patients. Among 37 SRNS patients, 30(81.0%) showed a final remission state with long-term steroid therapy, including methylprednisolone pulse therapy, over 4 months, with or without cytotoxic therapy. CONCLUSION: Almost half of the cases of childhood nephrotic syndrome requiring renal biopsy were not diagnosed with MCD. Among atypical features, hematuria and steroid-resistance would be the most probable indicators for a diagnosis other than MCD. Even in patients with SRNS, long-term methylprednisolone pulse therapy may result in a good remission rate.

A Case of Acute Postobstructive Pulmonary Edema due to Parapharyngeal Abscess in a Child / 소아알레르기및호흡기학회지

Postobstructive pulmonary edema (POPE) is associated with upper airway obstruction and has two different types of mechanism. Type 1 POPE is due to acute airway obstruction and is related to forceful respiratory efforts leading to extremely negative intrathoracic pressure. Type 2 POPE is caused by chronic airway obstruction and occurs after sudden relief of obstruction which drop in airway pressure that can lead to pulmonary edema. We report a case of postobstructive pulmonary edema in a child who has peripharyngeal abscess.

Chloroplast Cu/Zn-superoxide dismutase is a highly sensitive site in cucumber leaves chilled in the light.

Light-chilling stress, the combination of low-light illumination and low temperature, preferentially inactivated photosystem I (PSI) of cucumber (Cucumis sativus L.) leaves, resulting in the photoinhibition of photosynthesis. The extent of PSI photoinhibition, determined in vivo by monitoring absorption changes around 810 nm (induced by far-red light), was closely correlated with the redox state of the PSII electron acceptor Q(A), measured as the chlorophyll fluorescence parameter, 1-qP, where qP is a photochemical quenching coefficient. In contrast, the decrease in the far-red-induced leaf absorptance signal was not well correlated with the limited fragmentation of the PsaA/B gene products in the PSI reaction center after the light-chilling stress. Amongst various enzymes involved in the photooxidative damage such as superoxide dismutase (SOD), ascorbate peroxidase, and NAD(P)H dehydrogenase, only SOD was inhibited by light-chilling treatment. Further, an approximately 3-fold increase in the leaf content of H(2)O(2), a potent inhibitor of Cu/Zn-SOD, was observed after light-chilling stress. From these results, we suggest that Cu/Zn-SOD is the primary target of the light-chilling stress, followed by subsequent inactivation of PSI by reactive oxygen species.