Hypoglycemics medicinal chemistry

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Hypoglycemic Agents Gisvold’s book Insulins Synthetic oral hypoglycemics Top 200 Drug List

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Insulin Synthesized by islets  -cells from a 86-amino acid proinsulin Consists of chains A and B, with 21 and 30 amino acid residues, respectively The chains are connected by two disulfide linkages ( A7-B7 and A20-B19 ), and an intramolecular disulfide linkage ( A6-A11 ) The monomer is the biologically active form Receptor binding region include: A-1 Gly, A-4 Glu, A-5 Gln, A-19 Tyr, A-21 Asn, B-12 Val, B-16 Tyr, B-24 Phe, and B-26 Tyr Amino acid units can not be removed from the chain A without significant loss of activity. However, up to the first six and last three amino acid units from chain B can be removed without significant loss of activity

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Regular Insulin Onset and duration of insulin is controlled by absorption rate The absorption rate of insulin from subcutaneous site is slow because insulin molecules tend to form dimers and in the presence of zinc they form hexamers Only monomers and dimmers are absorbed with any degree of speed The dissociation rate is slow, onset is about 30 minutes and duration is about 6-12 hr, which is much longer than predicted by the half-life (~ 4 min) Insulin lispro, aspart, glulisine Human Insulin

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Insulin Lispro, Aspart, Glulisine Insulin Lispro (Humalog® ) : Lysine and proline exchanged at positions B28 and B29 and the equilibrium shifts away from hexamer formation thus enhances the rate at which it dissociates into dimers and then into monomers and the rate of absorption is increased

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Insulin Aspart (NovoLog® ): Aspartate is substituted for proline at B28 that shifts the equilibrium away from hexamer formation that reduces the tendency to form hexamers and thus increases the rate of absorption.

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Insulin Glulisine (Apidra®) : Lysine is substituted for asparagine at B3 and glutamate is substituted for lysine at B29 . Shifts the equilibrium away from hexamer formation and thus rapidly absorbed

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Insulin Glargine (Lantus®) NPH Insulin and Insulin glargine effects on Plasma Glucose Insulin glargine has the following substitutions: Asparagine at A21 is replaced with glycine Two arginines are added to the C terminus of the B chain These two changes make the molecule soluble only at a slightly acidic pH ( product pH 4 ) A long acting, delayed onset, insulin with a relatively flat plasma level profile over 24 hours Solution is clear but is not for intravenous use

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NPH and Insulin Zn Suspension Neutral Protamine Hagedorn (NPH) Insulin : Also called Isophane insulin suspension. Iso means same and phane means appearance (from the Greek). Particle size of ~ 30 μm and not for intravenous injection. Derived from protamine zinc insulin (PZI) but with careful control of protamine and insulin ratios. Protamine is a basic protein found in fish testes. The protamine zinc precipitate crystals are stable even when mixed with regular insulins . So premixed solutions can be prepared to give a rapid onset with longer duration. Insulin Zinc Suspension : Not for intravenous injection. There are three types: lente , semilente and ultralente . Semilente has a particle size of 2 μm; low concentrations of zinc used to form precipitate. Ultralente has a particle size of ~10-40 μm; high concentrations of zinc used to form precipitate. Lente is a 70:30 mix of Ultralente and semilente. Lente and NPH are incompatible due to different buffers. All Lentes has an excess of zinc so mixing with regular results in conversion of the regular to lente. However, mixing is not recommended . If mixed draw regular first and use immediately . Reaction of lente with regular is unpredictable in rate and may take 24 hr to equilibrate.

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Quick-acting, such as the insulin analog lispro -- begins to work within 5 to 15 minutes and is active for 3 to 4 hours. Short-acting, such as regular insulin -- starts working within 30 minutes and is active about 5 to 8 hours. Intermediate-acting, such as NPH , or lente insulin -- starts working in 1 to 3 hours and is active 16 to 24 hours. Long-acting, such as ultralente insulin -- starts working in 4 to 6 hours, and is active 24 to 28 hours. Insulin glargine starts working within 1 to 2 hours and continue to be active, without peaks or dips, for about 24 hours. A mixture of NPH and regular insulin -- starts working in 30 minutes and is active 16 to 24 hours. There are several variations with different proportions of the mixed insulins Summary of Insulin Activity

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Incretins and GLP-1 Incretins are a group of gastrointestinal hormones that cause an increase in the amount of insulin released from the beta cells of the islets of Langerhans after eating. They also inhibit glucagon release from the alpha cells. Glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP) are two main candidate molecules that are incretin mimics, but are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4 ). Two long-lasting analogs of GLP-1 , exenatide ( Byatta , 39-AA peptide, 2005) and liraglutide ( Victoza , 2010), are currently approved for use in the U.S. by subcutaneous injection. Sitagliptin (Januvia, 2006) is a DPP-4 inhibitor can be taken orally as a tablet. sitagliptin

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Oral Hypoglycemics Guanidine Galegine Pentamidine Sulfaisopropylthiadiazole Carbamide Killed patient through severe hypoglycemia First sulfonylurea to be marketed

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Sulfonylureas Contain a sulfonyl and a urea group The sulfonylurea portion is very water soluble , it has an acidic amine and oxygen atoms for good hydrogen bonding R 1 and R 2 are very lipophilic and account for differences in overall potency, metabolism, duration and routes of elimination Overall the drugs tend to be lipophilic and ionized at body pH They are weak acids with a pKa ~ 5–6 2nd generation are much more lipophilic than the 1st and hence more potent They stimulate the secretion of insulin from the functioning  -cells of the intact pancreas. Sulfonylureas are similar in chemistry to the sulfonamides and, thus, potentially share toxicities and allergies

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SAR of Sulfonylureas R1 Must be lipophilic Must have an aromatic ring next to the sulfoxide group. All marketed drugs have a phenyl ring Should have a substituent at the para position. Methyl , amino , acetyl , chloro , bromo , methylthio and trifluoromethyl enhance hypoglycemic activity The larger , more complex , para substituents comprise the 2nd generation . The ethylcarboxamide appears to be very potent in these drugs which may be due to the distance from the carboxamide nitrogen to the sulfonamide nitrogen and how it binds to the receptor R2 Must be lipophilic Has some size constraints: N-methyl is inactive , N-ethyl has low activity , N-dodecyl and above are inactive N-Propyl to N-hexyl are the most potent

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Sulfonylurea Drugs 1 st Generation In general these are eliminated in the urine as some parent compound plus metabolites Tolbutamide is one of the least potent oral hypoglycemics with short duration due to rapid hydroxylation of para methyl substituent followed by oxidation to the acid In Chlorpropamide the para chloro protects from oxidation and thus has a longer duration than tolbutamide. Also increases lipid solubility to increase potency . Metabolism is by ω and ω-1 oxidation Tolazamide has a cyclic substituent that makes it approximately equal to chlorpropamide in potency even though the para substituent is the same as tolbutamide. Oxidized quickly as with tolbutamide, but the alcohol formed has reasonable activity ( active metabolite ) so its overall duration is longer than tolbutamide and shorter than chlorpropamide Acetohexamide possesses ketone group that is rapidly reduced to the alcohol but this is more active than the parent compound and has a longer half-life . The 4 position on the hexane ring is also hydroxylated. Duration is similar to tolazamide .

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2 nd Generation Due to their larger molecular size, biliary excretion becomes important Glyburide and glipizide are hydroxylated at the 3 or 4 position on the cyclohexyl ring. Some metabolites are active so duration is longer than parent compound Glimepiride , sometimes referred to as a 3 rd generation , is most potent of all sulfonylureas. The cyclohexyl methyl is hydroxylated then oxidized to the acid.

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THIAZOLINEDIONES Does not increase insulin release like the sulfonylureas but increases the response to insulin . Example Pioglytazone (Actos) and rosiglitazone (Avandia). On November 19, 2007 an Advisory Committee of the FDA issued a “Black Box Warning”. On September 11, 2007, a research found diabetes drug Actos (by Takeda Pharmaceutical Co.) cuts the risk of heart attack, stroke and death, but raises the risk of heart failure, while rival Avandia (by GlaxoSmithKline) raises heart risks. "Although drugs may be in the same class, they also can have different clinical effects due to differences in molecular structure," said Mehmood Khan, M.D., Takeda Global Research & Development (TGRD) president.

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Contains a bisguanide in the structure where two molecules of guanidine linked together, e.g., Metformin (Glucophase). They reduce sugar absorption from GI tract, reduce gluconeogenesis and increase muscle and fat cell uptake of blood glucose and thus are antihyperglycemic rather than hypoglycemics Similar mechanism of action as the sulfonylureas without their toxicities BISGUANIDES Guanidine Bisguanide MEGLITINIDES Meglitinide

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 -Glucosidase Inhibitors Polysaccharides are broken down to smaller saccharides  -Glucosidase breaks down more complex saccharides in the intestine such as tri− and disaccharides by splitting off a single sugar from the end These drugs, by mimicking the sugar structure, bind with a higher affinity than the natural substrate to the enzyme, inhibiting further breakdown of these saccharides This decreases the absorption of monosaccharides and decreases the postprandial peak in blood glucose. Thus most useful in patients with postprandial hyperglycemia. Note that monosaccharides already in the diet are not affected and so patients should avoid eating glucose, itself Unfortunately, these drugs can increase the amount of saccharides entering the colon, and can cause colonic distress, which includes diarrhea, flatulence, and cramping

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Case 1. As staff pharmacist at the local hospital, you have been called in to consult on a case involving a 63-year-old itinerant farm worker who was brought in with symptoms of “insulin shock,” that is, confusion, disorientation, and convulsions. His blood glucose was 30 mg/100 ml. The symptoms were gradually reversed with IV glucose (5%). From a review of the record, you learn that the patient had been hospitalized 1 month earlier with acute pulmonary aspergillosis. This was treated with amphotericin B (slow IV) over a 2-week period. The patient was then released with a prescription for oral itraconazole ( 1 ) (two 100-mg tablets twice daily) for 2 months. Inspection of chart also revealed that the patient is an adult onset diabetic, who has been taking tolbutamide ( 2 ) (500 mg four times daily) for the past 5 years. Explain fully the likely cause of the hypoglycemic crisis Suggest approaches by which the type II diabetes can be controlled and the prophylaxis of the aspergillosis continued on an outpatient basis Chose the best oral hypoglycemic from 3-7 for this patient to co-administer with itroconazole

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Study Guide Structure and activity of regular insulin The pharmacokinetic profiles, SAR and chemistry of different types of insulin preparations What do you mean by glucagon like peptide? What is their function? What is the mechanism of sitagliptin? SAR of oral hypoglycemic agents Structures of oral hypoglycemic agents in top 200 list SAR in general and also for the individual drugs Mechanism of actions of all the drug classes Why rosiglitazone has black box warning? What is that warning?

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