Anti-Diabetic Agents PDF

Insulin and anti-diabetic medicines  Insulin and anti-diabetic medicines  Insulin and anti-diabetic medicines play crucial roles in managing diabetes, a metabolic disorder characterized by high blood sugar levels. 1. Insulin:  Insulin is a peptide hormone produced by t...

Insulin and anti-diabetic medicines  Insulin and anti-diabetic medicines  Insulin and anti-diabetic medicines play crucial roles in managing diabetes, a metabolic disorder characterized by high blood sugar levels. 1. Insulin:  Insulin is a peptide hormone produced by the pancreas that regulates glucose metabolism.  In people with diabetes, insulin production or function is impaired, leading to high blood sugar levels. Mechanism of Action:  Insulin binds to insulin receptors on cell membranes, facilitating the uptake of glucose into cells.  It enhances glucose storage as glycogen in the liver and muscle, and inhibits glucose production by the liver.  Insulin promotes fat storage and protein synthesis, while inhibiting the breakdown of fats and proteins. Synthetic Insulins:  In medicinal chemistry, synthetic forms of insulin have been developed to mimic the action of natural insulin. These include: 1. Rapid-acting insulins: Lispro, Aspart, Glulisine. 2.Long-acting insulins: Glargine, Detemir, Degludec.  These insulins have been chemically modified to alter their pharmacokinetic profiles (e.g., onset, duration of action) to better mimic physiological insulin release. 2.Oral Anti-diabetic Drugs: Several classes of oral anti-diabetic drugs are used to manage Type 2 diabetes, where insulin resistance or impaired insulin secretion is the primary issue.  These classes of drugs act via different mechanisms: Biguanides (e.g., Metformin): Mechanism: Metformin increases insulin sensitivity, reduces hepatic glucose production, and improves glucose uptake by muscles. Metformi n 1. Biguanide Core Structure:  The biguanide group (-N=C(NH2)-NH-C(NH2)=NH-) is central to metformin's function.  This group is essential for metformin's antihyperglycemic effect.  The biguanide core interacts with cellular targets involved in glucose metabolism, particularly AMP-activated protein kinase (AMPK).  AMPK activation reduces hepatic gluconeogenesis and increases peripheral glucose uptake, leading to improved insulin sensitivity. AMP-activated protein kinase (AMPK) is a phylogenetically conserved fuel- sensing enzyme that is present in all mammalian cells. 2. Lack of Lipophilic Groups:  Metformin is a highly hydrophilic molecule due to the absence of lipophilic (fat-soluble) groups.  This affects its absorption and transport, as metformin relies on organic cation transporters (OCT1 and OCT2) for cellular uptake, particularly in the liver and kidneys.  The hydrophilic nature also limits metformin’s permeability across lipid membranes, preventing significant distribution in adipose tissue and non-target areas. 3. Small Molecular Weight:  Metformin's small molecular weight (about 129 Da) contributes to its ability to be efficiently absorbed, although its bioavailability is moderate (40-60%) due to first-pass metabolism in the liver. 4. Amine Groups:  Metformin contains multiple amine groups (NH2) attached to its biguanide backbone. These groups are protonated under physiological conditions, making metformin positively charged.  The positive charge aids in its transport through cationic transporters like OCTs.  These amine groups are also important for metformin's solubility in water, ensuring good distribution in the bloodstream and effective renal excretion. 5.Resistance to Metabolism:  Metformin is not metabolized significantly in the liver, which contributes to its long half-life and duration of action.  Its chemical structure renders it resistant to enzymatic degradation, allowing it to be excreted unchanged in urine. Sulfonylureas (e.g., Glibenclamide, Glipizide): Mechanism: Sulfonylureas stimulate insulin release from pancreatic beta cells by closing ATP-sensitive potassium channels. Glibenclami de Glipizide 1. Sulfonylurea Group:  The core structure of sulfonylureas contains a sulfonamide group (-SO2NH-) connected to a urea moiety (-NHCONH-), forming the sulfonylurea backbone.  The sulfonylurea group is essential for the drug’s ability to bind to the SUR1 receptor (sulfonylurea receptor 1) on pancreatic beta cells, which is a subunit of the ATP-sensitive potassium (K_ATP) channels.  Binding to this receptor closes the K_ATP channels, leading to membrane depolarization, calcium influx, and insulin release. 2. Aromatic Ring (R1 Group):  Attached to the urea moiety is an aromatic ring (R1 group), which is critical for binding affinity and selectivity for the SUR1 receptor.  For glipizide, this aromatic ring is substituted with a para-methyl group (p-CH3).  This substitution enhances the potency and improves the interaction with the SUR1 receptor compared to first-generation sulfonylureas (e.g., tolbutamide). 3. Cyclohexyl Methyl Group (R2 Group):  On the other side of the sulfonyl group, at the R2 position, glipizide contains a cyclohexyl methyl group.  The cyclohexyl group contributes to the lipophilicity and metabolic stability of glipizide. It also increases the drug's binding affinity for the SUR1 receptor, contributing to its potency as a second-generation sulfonylurea. 4. Lipophilicity:  Second-generation sulfonylureas like glipizide are more lipophilic compared to first-generation drugs.  This increased lipophilicity results in better membrane permeability and allows for more effective receptor binding, making glipizide more potent.  The lipophilicity also influences the drug’s absorption and distribution, with rapid onset and shorter half-life compared to other sulfonylureas. 5. Shorter Half-Life:  The presence of a cyclic structure (cyclohexyl ring) gives glipizide a shorter half-life, which reduces the risk of prolonged hypoglycemia compared to Glyburid other sulfonylureas like glyburide. e 6. Para-Substituent on Phenyl  Ring: The para-methyl group (CH3) attached to the phenyl ring in glipizide is a feature common in second-generation  sulfonylureas. This substituent improves receptor affinity and reduces side effects compared to larger, bulkier groups. Thiazolidinediones (TZDs, e.g., Pioglitazone): Mechanism: TZDs act as PPAR-γ (peroxisome proliferator-activated receptor gamma) agonists, increasing insulin sensitivity in adipose tissue, Pioglitazon muscle, and liver. e 1. Thiazolidinedione (TZD) Ring:  The thiazolidinedione core (5-membered ring containing nitrogen and sulfur) is essential for binding to the PPAR-γ receptor.  The carbonyl groups on this ring play a critical role in the interaction with the ligand-binding domain of the PPAR-γ receptor.   This interaction helps modulate gene transcription related to glucose and lipid metabolism.  The TZD ring also facilitates insulin sensitization by promoting glucose uptake in peripheral tissues. 2. Aryl Alkyl Side Chain (Phenyl Ring and Linker):  Pioglitazone features a phenyl ring attached via a flexible methylene linker  This aryl alkyl side chain contributes to the drug’s affinity for the PPAR-γ receptor.  Substitutions on the phenyl ring, such as pyridyl substitution, can influence the selectivity and potency of the drug.  Pioglitazone contains a 2-pyridyl group on the phenyl ring, which increases binding efficiency to PPAR-γ and improves its pharmacological profile. 3. Pyridyl  Ring: The pyridyl group (a nitrogen-containing aromatic ring) is attached to the phenyl ring of the aryl alkyl  side chain. This structural feature enhances the drug's affinity for PPAR-γ and helps with the receptor-binding interactions that mediate insulin-sensitizing effects  The pyridyl ring also contributes to the overall lipophilicity of the molecule, influencing its absorption, distribution, and metabolism. 4. Linker Chain (Alkyl Chain):  The methylene (-CH2-) linker connecting the thiazolidinedione ring to the phenyl group ensures flexibility in the drug’s structure, allowing the proper alignment of the active site with the PPAR-γ  receptor. This flexibility is crucial for optimal receptor binding and activation, leading to enhanced therapeutic efficacy. 5. Lipophilicity and Partition Coefficient: The lipophilic nature of pioglitazone is important for membrane permeability, allowing the drug to cross lipid bilayers and interact with intracellular receptors like PPAR-γ.  Pioglitazone’s balance of hydrophobic and hydrophilic properties enhances its bioavailability and receptor interaction in target tissues. DPP-4 Inhibitors (e.g., Sitagliptin, Saxagliptin): Mechanism: Inhibit the enzyme DPP-4 (dipeptidyl peptidase-4), which breaks down incretin hormones. This leads to increased insulin secretion and reduced glucagon Sitaglipti n release. 1.Triazolopiperazine Ring:  The triazolopiperazine core in sitagliptin plays a crucial role in binding to the DPP-4 enzyme’s active site.  The triazole ring is critical for forming Saxaglipti interactions with the enzyme, specifically n hydrogen bonds and hydrophobic interactions.  The piperazine moiety offers conformational flexibility, allowing sitagliptin to fit into the DPP-4 binding pocket. 2.Fluorophenyl Group:  A trifluorophenyl group is attached to the triazolopiperazine structure, contributing to hydrophobic interactions within the DPP-4 active site. This group helps increase the affinity and selectivity of sitagliptin for DPP-4.  The electron-withdrawing nature of the fluorine atoms also improves metabolic stability by preventing oxidation, enhancing the drug's pharmacokinetic properties. 3.Carbonyl Functionality:  The presence of a carbonyl group near the triazole ring enhances the drug's binding to the enzyme through hydrogen  bonding interactions. This carbonyl functionality is important for anchoring the drug in the enzyme’s active site, improving the inhibitory action against DPP-4. GLP-1 Receptor Agonists (e.g., Exenatide, Liraglutide): Mechanism: Mimic GLP-1 (glucagon-like peptide-1), increasing insulin secretion and reducing glucagon levels. Chemical Structure: Modified peptides that resist degradation by DPP-4, prolonging their activity. SGLT2 Inhibitors (e.g., Dapagliflozin, Empagliflozin): Mechanism: Inhibit sodium-glucose co- transporter 2 (SGLT2) in the kidneys, Dapagliflozin reducing glucose reabsorption and increasing urinary glucose excretion. Chemical Structure: Contain a glucose moiety that interacts with the SGLT2 Empagliflozin protein, along with lipophilic groups to enhance binding.