• 약학회지
• /
• 제36권6호
• /
• pp.518-528
• /
• 1992

To determine the optimal conformation of sulfonylureas, the correlation between conformation and hypoglycemic activity of the two sulfonylureas of tolbutamide and chlorpropamide as hypoglycemic agent was studied using an empirical potential function (ECEPP/2) and the hydration shell model in the unhydrated and hydrated states. The conformational energy was minimized from several starting conformations with possible torsion angles in each molecule. The conformational entropy change of each conformation was computed using a harmonic approximation. To understand the hydration effect on the conformation of the molecules in aqueous solution, the contribution of water-accessible volume of each group or atom in the lowest-free-energy conformation was calculated and compared each other. From comparison of the computed lowest-free-energy conformations of two sulfonylureas, it could be suggested that the hydration of sulfonylurea moiety is related to increase the hypoglycemic activity. From the calculation results, it was known that the conformational entropy is the major contribution to stabilize the low-free-energy conformations of two sulfonylureas in unhydrated state. Whereas, in hydrated state, the hydration free energy largely contributes to the total free energies of low-free-energy conformations of tolbutamide and conformational entropy contributes to stabilize the low-free-energy conformations of chlorpropamide. The torsion angles from phenyl ring to urea moiety of the low-free-energy conformations of the two sulfonylureas were shown the nearly regular trend. On the basis of these results, the conformation exhibiting the optimal hypoglycemic activity of sulfonylureas and the binding direction to pancreatic receptor site A could be predicted. Also, according to the side chain lengthening of urea moiety, tolbutamide showed various conformational change. Therefore, steric effect may be important factor in the interaction between sulfonylureas and the putative pancreatic receptor.

• 약학회지
• /
• 제39권3호
• /
• pp.329-336
• /
• 1995

Conformational free energy calculations using an empirical potential function and a hydration shell model(program CONBIO) were carried out on hypoglycemic agent acetohexamide and tolazamide in the unhydrated and hydrated states. The initial geometry of sulfonylureas was obtained from X-ray crystallographieal data and homologous molecular fragments. In both states, the feasible conformations were obtained from the calculations of conformational energy, conformational entropy, and hydration free energy by varying all the torsion angles of the molecules. From the calculation results, it is known that the conformations] entropy is the major contribution to stabflize the low-free-energy conformations of two sulfonylureas in both states. But, in hydrated state, the hydration does not directly affect each conformations. The intramolecular hydrogen bonding of sulfonylurea hydrogen and 7-membered nitrogen appeared to the conformations of tolazamide in both states. It is thought that the hydrogen bonding decrease steric hindrance on the receptor binding direction. The substitution of alicyclic or N-heterocyclic ring than that of carbons chain of urea moiety may be properly interaction between sulfonylureas and the putative pancreatic receptor.

• The Korean Journal of Physiology and Pharmacology
• /
• 제19권3호
• /
• pp.197-202
• /
• 2015

Sulfonylureas are widely used as an antidiabetic drug. In the present study, the effects of sulfonylurea administered supraspinally on immobilization stress-induced blood glucose level were studied in ICR mice. Mice were once enforced into immobilization stress for 30 min and returned to the cage. The blood glucose level was measured 30, 60, and 120 min after immobilization stress initiation. We found that intracerebroventricular (i.c.v.) injection with $30{\mu}g$ of glyburide, glipizide, glimepiride or tolazamide attenuated the increased blood glucose level induced by immobilization stress. Immobilization stress causes an elevation of the blood corticosterone and insulin levels. Sulfonylureas pretreated i.c.v. caused a further elevation of the blood corticosterone level when mice were forced into the stress. In addition, sulfonylureas pretreated i.c.v. alone caused an elevation of the plasma insulin level. Furthermore, immobilization stress-induced insulin level was reduced by i.c.v. pretreated sulfonylureas. Our results suggest that lowering effect of sulfonylureas administered supraspinally against immobilization stress-induced increase of the blood glucose level appears to be primarily mediated via elevation of the plasma insulin level.

• 농약과학회지
• /
• 제5권2호
• /
• pp.33-36
• /
• 2001

2-Chloromethyl-1,3-dioxolane기가 치환된 새로운 thiophene sulfonylurea계 유도체들을 합성하였고, 신규 합성된 화합물을 발아전 토양처리와 발아후 경엽처리를 통하여 문제잡초 9종의 제초활성을 규명하였으며, 답작 조건의 이앙벼 및 주요 잡초에 대한 제초활성도 시험하였다. 이 화합물들의 제초활성은 헤테로고리의 치환기에 따라 매우 다르게 나타났는데, 4, 6 위치에 각각 dimethoxy, 혹은 methyl, methoxy가 치환된 pyrimidine, 혹은 triazine이 붙어있는 sulfonylurea들이 활성이 좋았다. 그러나 이들은 2-fluoromethyl-1,3-dioxolane기가 치환된 thiophene sulfonylurea계 유도체보다 일반적으로 제초활성이 약하게 나타났다.

• 한국임상약학회지
• /
• 제28권3호
• /
• pp.188-193
• /
• 2018

Background: Previous studies have noted that the simultaneous use of sulfonylureas and antimicrobials, which is common, could increase the risk of hypoglycemia. In particular, an age of 65 years or older is a known risk factor for sulfonylurea-related hypoglycemia in hospitalized patients. Therefore, we performed this study to determine the potential risk of hypoglycemia from the concurrent use of antimicrobials and sulfonylureas. Methods: We performed a cross-sectional study on the National Health Insurance Service-National Sample Cohort from 2013. The eligibility criteria included patients of 65 years of age or older taking a sulfonylurea with 25 different antimicrobials. Different risk ratings of severity in drug-drug interactions (potential DDIs), level X, D, or C in Lexi-$Interact^{TM}$ online, and contraindicated, major, or moderate severity level in $Micromedex^{(R)}$ were included. SAS version 9.4 was used for data analysis. Results: A total of 6,006 elderly patients with 25,613 prescriptions were included. The largest age group was 70 to 74 (32.7%), and 39.7% of patients were men. The mean number of prescriptions was 4.3 per patient. The most frequently used antimicrobials were levofloxacin (6,583, 25.7%), ofloxacin (6,549, 25.6%), fluconazole (4,678, 18.0%), and ciprofloxacin (2,551, 9.8%). Among sulfonylureas, glimepiride was prescribed most frequently, followed by gliclazide, glibenclamide, and glipizide. Conclusion: Of the antimicrobials with a high potential of hypoglycemia, levofloxacin, ofloxacin, fluconazole, and ciprofloxacin were used frequently. Thus, the monitoring of clinically relevant interactions is required for patients concurrently administered sulfonylureas and antimicrobials.

• Bulletin of the Korean Chemical Society
• /
• 제20권3호
• /
• pp.273-275
• /
• 1999

• 한국임상약학회지
• /
• 제25권2호
• /
• pp.74-79
• /
• 2015

Objective: Treatment with sulfonylureas in combination with metformin improves glycemic control in type 2 diabetes mellitus (T2DM), but is associated with hypoglycemia and weight gain. This retrospective study aims to compare the effectiveness of dipeptidylpeptidase-4 (DPP-4) inhibitors and sulfonylureas as an add-on therapy to metformin in patients with T2DM. Methods: Data from medical records of 355 T2DM patients received therapy either DPP-4 inhibitors (DPP-4 inhibitor group) or sulfonylurea (SU group) in combination with metformin from 1 March 2009 to 30 September 2011 were retrospectively reviewed. Of total 355 patients, 231 patients were in DPP-4 inhibitor group and 124 patients were in SU group. Baseline Hemoglobin $A_{1c}$ ($HbA_{1c}$) level in SU group was higher than DPP-4 inhibitor group with a statistically significant difference (8.6% vs. 7.8%). Comparative analysis between DPP-4 inhibitor group and SU group was performed for $HbA_{1c}$ values, amounts of $HbA_{1c}$ changes, and rates of $HbA_{1c}$ changes from baseline at 6-month intervals and incidence rates of major cardiocerebral events. Results: SU group showed larger $HbA_{1c}$ changes in both amounts and rates compared to DPP-4 inhibitor group, although statistical significance was not found in all study periods. Proportions of patients with stable $HbA_{1c}$ <6.5% or 7% were significantly higher in DPP-4 inhibitor group than SU group (<6.5%: 30.4% vs. 13.4%, <7%: 72.3% vs. 41.2%). Time to achieve stable $HbA_{1c}$ <6.5% was not significantly different, but time to achieve stable $HbA_{1c}$ <7% was shorter in DPP4 inhibitor group than SU group with a significant difference. The incidence rate of cardiocerebral events in group of patients with or without previous events was 1.7%, not significantly lower than that in DPP-4 inhibitor group (4.0%). For newly encountered cardiocerebral events during the treatment, incidence rates of two groups did not differ significantly. Conclusion: DPP-4 inhibitors were as effective as sulfonylureas in achieving the $HbA_{1c}$ goal of less than 6.5% or 7% and cardiocerebral event rates did not differ between the two drugs.

• Journal of Pharmaceutical Investigation
• /
• 제1권1호
• /
• pp.58-61
• /
• 1971

Comparatives studies were made on stabilities of some hormons, used individually and combined with some stabilizers, and the following results were found. 1. The increasing order of antiallergic hormons (prednisolone, dexamethasone) to the stabilities as follows : Chlorpheniramine>Menadione>Inositol>Ascorbic acid. 2. The increasing order of sulfonylureas in as follows : Chlorpheniramine>Thiamine>Inositol>Ascorbic acid.

• Asian-Australasian Journal of Animal Sciences
• /
• 제23권5호
• /
• pp.672-679
• /
• 2010

Diabetes mellitus is a worldwide epidemic with high mortality. As concern over this disease rises, the number and value of research grants awarded by the National Research Foundation of Korea (NRF) have increased. Diabetes mellitus is classified into two groups. Type 1 diabetes requires insulin treatment, whereas type 2 diabetes, which is characterized by insulin resistance, can be treated using a variety of therapeutic approaches. Hyperglycemia is thought to be a primary factor in the onset of diabetes, although hyperlipidemia also plays a role. The major organs active in the regulation of blood glucose are the pancreas, liver, skeletal muscle, adipose tissue, intestine, and kidney. Diabetic complications are generally classified as macrovascular (e.g., stroke and heart disease) or microvascular (i.e., diabetic neuropathy, nephropathy, and retinopathy). Several animal models of diabetes have been used to develop oral therapeutic agents, including sulfonylureas, biguanides, thiazolidinediones, acarbose, and miglitol, for both type 1 and type 2 diseases. This review provides an overview of diabetes mellitus, describes oral therapeutic agents for diabetes and their targets, and discusses new developments in diabetic drug research.

• 한국잡초학회지
• /
• 제15권1호
• /
• pp.54-62
• /
• 1995

분지 아미노산 생합성 효소인 ALS의 활성(活性)을 억제하는 sulfonylurea계 2약제 및 imidazolinone계 2약제를 대상으로 32초종에 대한 약제별 살초(殺草) 반응성 및 옥수수, 밀, 콩의 ALS 활성(活性) 억제 반응성을 통하여 ALS 활성(活性) 억제작용(抑制作用)과 살초작용(殺草作用)의 관계를 조사하였다. 1. Sulfonylurea계의 2가지 제초제(除草劑)들의 살초(殺草)스펙트럼은 적은 처리량에서도 매우 넓었으며, 내성(耐性)을 보였던 식물은 발아전 토양처리에서 밀, 보리, 개밀, 메귀리 등이었고, 발아 후 경엽처리에서 밀, 보리, 까마중, 왕바랭이, 개밀, 미국개가장, 메귀리 등이었다. 2. Imidazolinone계 2종의 제초제(除草劑)들에 대하여 내성(耐性)을 보였던 식물은 발아 전 처리에서 콩, 자귀풀, 도깨비바늘, 메귀리, 개밀 등이었고, 발아후 처리에서 콩, 자귀풀, 크로바 등으로 두과식물이었다. 3. Sulfonylurea 및 imidazolinone계 제초제(除草劑)들에 대하여 공통적으로 감수성(感受性)인 식물은 옥수수와 수수, sulfonylurea계에 감수성(感受性)을 보이면서 imidazolinone계에 내성(耐性)을 보였던 식물은 콩, 크로바, 자귀풀 등 두과식물이었다. 이와 대조적으로 sulfonylurea계에 내성(耐性)을 보이면서 imidazolinone계에 감수성(感受性)을 보였던 식물은 밀과 보리, 공통적으로 내성(耐性)을 보였던 식물은 개밀등 이었다. 4. Sulfonylurea계 약제에 대하여 온실 실험에 서 얻은 초종별 $GI_{50}$ 값과 각 초종으로부터 추출한 ALS 활성(活性) 억제 $IC_{50}$ 값은 경향이 일치하지 않았다. 5. Imidazolinone계 약제에 대하여 온실 실험에서 얻은 초종별 $GI_{50}$ 값과 각 초종으로부터 추출한 ALS 활성(活性) 억제 $IC_{50}$ 값은 경향이 유사(類似)하였다.