Sulfonylurea/ja

スルホニル尿素の一般構造式。官能基はスルホニル基とN-置換ウレイレン基からなる。

スルホニル尿素（sulfonylureas）は、医学や農業で用いられる有機化合物の一種である。官能基はスルホニル基（-S(=O)₂）からなり、その硫黄原子はウレイレン基（N,N-デヒドロ尿素、尿素の脱水素誘導体）の窒素原子に結合している。側鎖R₁とR₂は、様々なスルホニル尿素を区別する。 スルホニル尿素は最も広く使われている除草剤である。

農業用途

スルホニル尿素の多くは、特定のアミノ酸の植物生合成を阻害することができるため、除草剤としても使用されている。

除草剤としてのスルホニル尿素は、特にアセト乳酸合成酵素阻害を介してアミノ酸のバリン、イソロイシン、ロイシンの生合成を阻害することによって機能する。 このクラスの化合物には、アミドスルフロン、アジムスルフロン、ベンスルフロン-メチル、クロリムロン-エチル、クロルスルフロン、エタメツスルフロン-メチル、シノスルフロン、エトキシスルフロン、フラザスルフロン、フルピルスルフロン-メチル-ナトリウム、イマゾスルフロン、メトスルフロン-メチル、ニコスルフロン、オキサスルフロン、プリミスルフロン-メチル、プロスルフロン、ピラゾスルフロン-エチル、リムスルフロン、スルホメツロン-メチル、スルホスルフロン、チフェンスルフロン-メチル、トリアスルフロン、トリベヌロン-メチル、トリフルスルフロン-メチルがある。これらは、アセト乳酸合成酵素という酵素を阻害することによって植物の雑草や害虫を殺す広域除草剤である。1960年代には、1 kg/ha (0.89 lb/acre)以上の作物保護剤を散布するのが一般的であったが、スルホニルウレア剤では1%程度の散布量で同じ効果が得られる。

医薬用途

2型糖尿病の治療

これらは2型糖尿病の管理において抗糖尿病薬として広く使用されている。膵臓のβ細胞からのインスリンの分泌を増加させることによって作用する。

スルホニル尿素薬は、1型糖尿病や膵切除後のようにインスリン分泌が絶対的に不足している場合には無効である。

スルホニル尿素は、いくつかのタイプの新生児糖尿病の治療に用いることができる。歴史的には、高血糖で血中インスリン濃度が低い人は、デフォルトで1型糖尿病と診断されていたが、生後6ヵ月までにこの診断を受けた患者は、生涯を通じてインスリンではなくスルホニル尿素薬を投与される候補となることが多いことがわかっている。

2011年のコクランでは、システマティックレビューが行われた。成人の潜在性自己免疫糖尿病 (LADA)の治療効果が評価され、スルホニル尿素はインスリンと比較した場合、3ヵ月後および12ヵ月後のグルコースの代謝コントロールを改善せず、場合によってはHbA1c値を悪化させることさえあることが示された。同じレビューでは、スルホニルウレアによる治療後の空腹時Cペプチドの改善は認められていない。それでも、このレビューに含めることができた研究は、質とデザインにかなりの欠陥があったことを強調することは重要である。

While prior sulfonylureas were associated with worse outcomes, newer agents do not appear to increase the risk of death, heart attacks, or strokes. This is further reinforced by a 2020 Cochrane systematic review which did not find enough evidence of reduction of all-cause mortality, serious adverse events, cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke or end-stage renal disease when comparing metformin monotherapy to sulfonylureas. This same review also did not find improvement in health-related quality of life.

In individuals with impaired-glucose tolerance, a 2019 systematic review only found one suitable trial comparing the effects of Sulphonylurea with Metformin in reduction or delay of risk of developing type 2 diabetes, however this trial did not report patient-relevant outcomes. Another systematic review completed in the same year suggested that there is limited evidence if the combined used of Metformin with Sulphonylurea compared to the combination of Metformin plus another glucose-lowering intervention, provides benefit or harm in mortality, severe adverse events, macrovascular and microvascular complications. Combined Metformin and Sulphonylurea therapy did appear to lead to higher risk of Hypoglycemia.

Interleukin-1 β inhibitors

Sulfonylureas are also used experimentally to inhibit release of interleukin 1 beta from the NALP3 (or NLRP3) inflammasome.

Side effects

Sulfonylureas – as opposed to metformin, the thiazolidinediones, pramlintide and other newer treatments – may induce hypoglycemia as a result of excesses in insulin production and release. Hypoglycemia appears to happen more often with sulfonylureas than compared to other treatments. This typically occurs if the dose is too high, and the patient is fasting. Some people attempt to change eating habits to prevent this, however it can be counterproductive.

Like insulin, sulfonylureas can induce weight gain, mainly as a result of their effect to increase insulin levels and thus use of glucose and other metabolic fuels. Other side-effects are: gastrointestinal upset, headache and hypersensitivity reactions.

The safety of sulfonylurea therapy in pregnancy is unestablished. Prolonged hypoglycemia (4 to 10 days) has been reported in children borne to mothers taking sulfonylureas at the time of delivery. Impairment of liver or kidney function increase the risk of hypoglycemia, and are contraindications. Since other antidiabetic drugs cannot be used either under these circumstances, insulin therapy is typically recommended during pregnancy and in liver and kidney failure, although some of the newer agents offer potentially better options.

A 2011 Cochrane review found evidence that treatment of LADA using sulfonylureas lead to earlier insulin dependence in approximately 30% of cases.

A 2014 Cochrane review found tentative evidence that people treated with sulfonylureas have fewer non-fatal cardiovascular events than those treated with metformin (RR 0.7) but a higher risk of severe hypoglycemia (RR 5.6). There was not enough data available to determine the risk of mortality or of cardiovascular mortality. An earlier review by the same group found a statistically significant increase in the risk of cardiovascular death for first generation sulfonylureas relative to placebo (RR 2.6) but there was not enough data to determine the relative risk of first generation sulfonylureas relative to insulin (RR 1.4). Likewise it was not possible to determine the relative mortality risk of second generation sulfonylureas relative to metformin (RR 1.0), insulin (RR 1.0), or placebo. The FDA requires sulfonylureas to carry a label warning regarding increased risk of cardiovascular death.

A 2020 Cochrane systematic review comparing metformin monotherapy to sulfonylureas did not find enough evidence of reduction of all-cause mortality, serious adverse events, cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke or end-stage renal disease.

Second-generation sulfonylureas have increased potency by weight, compared to first-generation sulfonylureas. Similarly, ACCORD (Action to Control Cardiovascular Risk in Diabetes) and the VADT (Veterans Affairs Diabetes Trial) studies showed no reduction in heart attack or death in patients assigned to tight glucose control with various drugs.

Interactions

Drugs that potentiate or prolong the effects of sulfonylureas and therefore increase the risk of hypoglycemia include acetylsalicylic acid and derivatives, allopurinol, sulfonamides, and fibrates. Drugs that worsen glucose tolerance, contravening the effects of antidiabetics, include corticosteroids, isoniazid, oral contraceptives and other estrogens, sympathomimetics, and thyroid hormones. Sulfonylureas tend to interact with a wide variety of other drugs, but these interactions, as well as their clinical significance, vary from substance to substance.

Structure

Sulfonylureas contain a central S-arylsulfonylurea structure with a p-substituent on the phenyl ring (R¹) and various groups terminating the urea N′ end group (R²). Chemically, this functionality can be easily installed by reacting aryl sulfonamides (R¹—C₆H₄—SO₂NH₂) with isocyanates (R²—NCO).

• 
  Chlorpropamide (1st generation)
• 
  Tolazamide (1st generation)
• 
  Gliclazide (2nd generation)
• 
  Glimepiride (2nd generation)

Classification

Sulfonylureas are divided into 3 classes on basis of therapeutic efficiency of their antidiabetic action:

• First-generation drugs:

They include acetohexamide, carbutamide, chlorpropamide, glycyclamide (tolcyclamide), metahexamide, tolazamide and tolbutamide.

• Second-generation drugs:

They include glibenclamide (glyburide), glibornuride, gliclazide, glipizide, gliquidone, glisoxepide and glyclopyramide.

• Third-generation drugs:

They include glimepiride, although it is sometimes considered a second-generation drug.

Mechanism of action

Diagram of glucose reduction and insulin release in the pancreas

Sulfonylureas bind to and close ATP-sensitive K⁺ (K_ATP) channels on the cell membrane of pancreatic beta cells, which depolarizes the cell by preventing potassium from exiting. This depolarization opens voltage-gated Ca²⁺ channels. The rise in intracellular calcium leads to increased fusion of insulin granules with the cell membrane, and therefore increased secretion of mature insulin.

There is some evidence that sulfonylureas also sensitize β-cells to glucose, that they limit glucose production in the liver, that they decrease lipolysis (breakdown and release of fatty acids by adipose tissue) and decrease clearance of insulin by the liver.

The K_ATP channel is an octameric complex of the inward-rectifier potassium ion channel K_ir6.x and sulfonylurea receptor SUR which associate with a stoichiometry of 4:4.

Furthermore, it has been shown that sulfonylureas interact with the nucleotide exchange factor Epac2. Mice lacking this factor exhibited a decreased glucose-lowering effect upon sulfonylurea treatment.

History

Sulfonylureas were discovered in 1942, by the chemist Marcel Janbon and co-workers, who were studying sulfonamide antibiotics and discovered that the compound sulfonylurea induced hypoglycemia in animals.

Research and development (translational research and commercial application development) for sulfonylureas as pharmaceuticals (as diagnostic and therapeutic agents in prediabetes and diabetes) happened in the 1950s and 1960s, as explored at Tolbutamide § History.

Research and development (translational research and commercial application development) for sulfonylureas as herbicides happened in the 1970s and 1980s, as explored for example in a volume of the Sloan Technology Series focusing on the sociotechnological aspects of agriculture (Canine 1995); the DuPont Experimental Station led this development.