Chapter -11 - Medicinal chemistry -2 B.Pharmacy -V semester

1. CHAPTER -11 :
ANTIDIABETIC DRUGS
Prepared and submitted by
S.D.Shanmugakumar, M.Pharm., Ph.D
Associate professor,
Department of Pharmaceutical Chemistry
Jyothishmathi Institute of Pharmaceutical
sciences,
Thimmapur, Karimnagar - 505527

2. Chapter -11 : Antidiabetic agents
Antidiabetic agents comprise a chemically and pharmacologically heterogeneous group of drugs. The
objective in treating diabetes mellitus is to prevent undue rises in blood glucose throughout each
successive 24-hour period, without producing clinical hypoglycemiaHollander (1998). It is now widely
accepted that good control of blood glucose prevents the development of microvascular
(retinopathy, nephropathy) and neuropathic long-term complications of the disease in both type 1.
In type 1 diabetes, where there is absent or little endogenous beta-cell function, insulin treatment is
essential to prevent diabetic ketoacidosis, and the aim is the precise replacement of insulin in the
fasting state and after meals.
In type 2 diabetes, a choice of treatments, including insulin, is available. These comprise drugs that
increase insulin secretion (sulfonylureas, such as glibenclamide, glipizide, gliclazide, and the
meglitinide-like drugs, such as repaglinide and nateglinide), drugs that improve insulin sensitivity
(biguanides, e.g., metformin), the thiazolidinediones, such as rosiglitazone, pioglitizone, and
troglitazone), and drugs that reduce carbohydrate absorption (acarbose). In type 2 diabetes, choice
of therapy depends on several factors (pregnancy and presence of obesity) and combinations of
agents are often used to achieve better control than when one agent is used alone (e.g., insulin plus
sulfonylurea, sulfonylurea plus metformin). Within each category of agent, choice is often related to
pharmacokinetic considerations (gliclazide is short acting, whereas chlorpropamide and
glibenclamide have long half-lives; there are numerous formulations of insulin producing a very short
duration of action to an extremely long duration of action). Theoretically, an ideal agent would be
one with a short duration of action and administered in association with each meal. However, patient
convenience may take precedence over tight blood glucose control. New approaches include the use
of glucagon-like peptide 1 (GLP-1) and its long-acting natural and synthetic analogues such as exendin
4, LY315902, and NN2211, which are undergoing evaluation.

4. Types of diabetes : Polydipsia, polyurea, ketnemia and ketourea.
1. Insulin dependent diabtes mellitus ( Type –I ) diabetes - It is an auto –immune
disease caused by the pancreatic islet cells.
2. Non –Insulin dependent diabetes mellitus ( Type –II daibetes) – Due to insulin
resistance and loss of secretory fucntion by pancreatic –Beta cells.
HbA1C = below 7%

5. Hypoglycemic agents
Hypoglycemic agents or antidiabetic agents lower the blood sugar and are used to treat
the symptoms of diabetes mellitus.
Pharmacological treatment of type –I diabetes requires intensive insulin therapy. The
large number of short and long acting insulin are used for multiple doses for reducing
sugars before and after food.
Medical treatment of type 2 diabetes requires the management of hyperglycemis at
the patients HbA1C below 7%.
Classification:
Drugs for diabetes mellitus - Insulin
Long acting
Intermediate
Rapid Lispro
NPH lente
glargine

6. Non-Insulin antidiabetic drugs
1. Insulin secretagogues – Glipizide
2. Biguanides – Metformin
3. alpha –Glucosidase inhibitors – acarabose
4. Thiazolidine diones – Pioglitazone
5. Amylin analogs –Pramlinitidine
6. Incretin Modulators
7. Sodium glucose co-transporter 2 inhibitors – Dapagliflozin, Canagliflozin
8. DPP4- inhibitors – Vidagliptin, Saxgliptin, sitagliptin
9. GLP-1 ( Glucagon –like peptide -1) – Exenatide, Lixisenatide
10. Glucokinase inhibitors –Hexokinase –IV
11. DUAL PPAR agonists – Saroglitazar
12. Dopamine – 2- receptor agonist.

7. Insulin and its preparations
The insulin molecule consists of two chains – Polypetide A and B. they are linked
together by two disulfide bonds :
1. Chain A = 21 amino acids
2. Chain B = 30 amino acids
Molcular weight – 5734 daltons
It is biosynthesized from beta –cells of the pancreas from pre pro insulin –
110 amino acids chains with 12,000 daltons. It get cleaved in the endoplasmic
reticulum losing a 24 amino acids from the N- terminal. It has a losing four basic amino
acids – ArgB31, Arg B32, LysA64 and prohormone convertases PC1 and PC2.

8. Insulin -Moorsl

10. Sources : It is obtained from bovine –based or porcine –based insulin. The biosynthetic
insulins are : Biosynthetic human, semisynthetic human and analogs of human insulin.
Types of insulin:
1. Rapid acting insulin anlogs : Insulin lispro, Insulin aspart, Insulin glulisine.
Insulin lispro – lysB29 switched with Pro B 28 ( 5-15 min)
Insulin aspart – The pro B 28 has substituted with Asp (5-15min)
Insulin Glulisine – Val B3 is substituted with a Lys ( 15 min)
Lys B29 coupled with glutamate.
Short-acting insulin:
Insulin NPH – Equal amounts of the positively charged polypeptide protamine to
regular insulin (30-60min)
Insulin lente (30-60min) –regular insulin and zinc in an acetate buffer.

11. Long acting insulin :
Insulin gargline:
Replacement of AsnA21 by glycine and the two Arg amino acids to
the C-terminus of the B chain ( 0.8-2hrs).
Insulin ultralente :
Long-acting insulin that is 4-zinc acetate crystalline product.
Insulin detemer :
N-acetylation of Lys B29 with the 14- carbon mystic acid.
Premixed insulins :
Mixture of NPH and lispro can be 50:50 or 75:25

12. Oral hypoglycemic agents
The insulin secretagogues includes the sulfonyl ureas and meglitinides both increase
insulin release from the pancreas by a common mechanism:
Mechanism of Action:
All of the sulfonyl ureas and meglinides are stimulate the release of insulin from B-
cells of the pancreas.
These cells metabolize glucose in mitochondria to produce ATP.
The intracellular ratio of ATP/ADP, resulting in the closure of the ATP – Sensitive K+
channel on the plasma membrane. Closure of this channel triggers the opening of
Voltage – sensitive Ca2+ channels leading to rapid influx of Ca2+. Increased
intracellular Ca2+ causes an alteration in the cytoskeleton and stimulates translocation
of insulin – containing granules to the plasma membrane and the exocytotic release of
insulin.
ATP- Sensitive K+ channel has two units of the binding site for both sulfonyl ureas
and ATP designated as the sulfonyl urea receptor – type -1 (SUR1)an inwardly
rectifying K+ channel.

16. Sulfonyl ureas
First generation : Tolbutamide, chlorpropamide
Second generation : Glipizide, Glimepiride
1. The benzene ring should contain one substituent, preferably at the para position (R).
2. The substituents that seem to enhance hypoglycemic activity are methyl, amino,
methyl, acetyl, chloro, bromo, methylthio, and trifluoromethyl groups.
3. Compounds with P-( β-arylcarboxamido ethyl) substituents have better activity than
the first generation agents.
4.The group attached to the terminal nitrogen (R2) should be certain size and should
impart lipophilic properties to the molecule.

17. Adverse effects :
Sulfonyl ureas are associated with weight gain, though less so than insulin.
Tolbutamide
3-Butyl-1- ( 4-methyl benzene sulkfonyl) urea

18. Metabolism
Metabolized in the liver principally via oxidation of the P-methyl group producing the
carboxyl metabolite.
Many of the metabolized to 4- hydroxy tolbutamide.
Uses:
For treatment of NIDDM – Non –insulin dependent diabetes mellitus)
Synthesis :

20. Chlorpropamide
1-(4- chlorobenzene sulfonyl) -3- propyl urea
Meatbolism : Chlorpropamide has a considerabley longer half –life than the
other sulfonyl ureas and has a greater tendency for adverse effects.
Uses : Treatment of NIDDM in conjuction with diet and exercise.

21. Glipizide
N-2(4-(Cyclohexylcarbamoyl) amino) sulfonyl) Phenyl) ethyl)-5-methyl pyrazine -2-
carboxamide.
Metabolism : Hepatic metabolism
Uses : Adjunct diet for the control of Hyperglycemia.

22. Metabolism
Hydroxylation of non-terminal
aliphatic carbon adjacent to
aromatic ring
Aliphatic
hydroxylation of
methyl carbon
adjacent to aromatic
ring
AndFromCyProduct
Hydroxylation of
alicyclic secondary
carbon
Hydroxyla
tion of
alicyclic
secondary
carbon
Hydroxylation of alicyclic secondary carbon

23. Glimepride
Metabolism : Glimepride is metabolized in the liver. Primarily in Cytochrome P2 C9 to
the active metabolite cyclohexyl hydroxy methyl derivative ( M-1) which is further
metabolized to the inactive metabolite carboxyl derivative.
Uses : Treatment of non- insulin dependent type diabetes mellitus.

24. Meglitinides
Repaglinide
2-ethoxy -4 ( 1s – 3-Methyl -1- ( 2- Piperidyl) – Phenyl) Butyl) carbamoyl)
methyl benzoic acid.
Metabolism : Repalinidine is rapidly metabolised via oxidation and dealkylation
cytochrome P4503 A4 and 2C9 to form the major dicarboxylic acid derivative
(M2)

25. Hydroxylation of
non-terminal
aliphatic carbon
adjacent to
aromatic ring
Aliphatic
hydroxylation of
methyl carbon
adjacent to aromatic
ring
AndFromCyProduct
Hydroxylation of alicyclic
secondary carbon
Hydroxylation
of alicyclic
secondary
carbon

26. Uses : As an adjunct to diet and exercise to improve glycemic control
Nateglinide
2- hydroxy -4(propan-2yl) cyclohexyl) methylidene) amino -3- phenyl propanoic acid.
Uses : For the treatment of NIDDM in conjuction with diet and exercise

27. Metabolism
O-Hydroxylation of
monosubstituted
benzene
Hydroxylation of non-
terminal aliphatic carbon
adjacent to aromatic ring
Hydroxylation of
alicyclic secondary
carbon
Hydroxylation of
alicyclic
secondary carbon

28. Insulin sensitizers ( PPAR) agonists
The thiazolidine diones are the classic examples of PPARg agonists and commonly
referred to as “ glitazones”. Thiazolidine diones are ligands of the perioxisome
proliferator – activayed receptor – gamma ( PPAR –γ) that is expressed in the
nucleus of adipocytes, myocytes and hepatocytes. PPARγ that regulates the
expression of genes involved in lipid and glucose metabolism, insulin signal
transduction and adipocyte differentiation.
MOA:
PPARγ is expressed in multiple tissue types ( skeletal muscle, fat & liver). Activation
of PPAR – Gammareceptors regulates the transcription of insulin- responsive genes
involved in the control of glucose production, transport and utilization.

29. Thiazolidiene diones is an increased expression of the glucose GLUT4. The increased
expression of GLUT4 in addition to mediators of insulin signal transduction increases the
ability of cells ( Adipocytes) which take up the glucose when stimulated by the insulin.

30. Rosiglitazone
5-(4-(2-(N-methyl-N (2-pyridyl) amino) ethoxy) benxyl)Thiazolidine -2,4 dione.
Rosiglitazone is an anti-diabetic drug in the thiazolidinedione class of drugs. It is
marketed by the pharmaceutical company GlaxoSmithKline as a stand-alone
drug (Avandia) and in combination with metformin (Avandamet) or with
glimepiride (Avandaryl). Like other thiazolidinediones, the mechanism of action
of rosiglitazone is by activation of the intracellular receptor class of the
peroxisome proliferator-activated receptors (PPARs), specifically PPARγ.
Rosiglitazone is a selective ligand of PPARγ, and has no PPARα-binding action.
Apart from its effect on insulin resistance, it appears to have an anti-
inflammatory effect: nuclear factor kappa-B (NFκB) levels fall and inhibitor (IκB)
levels increase in patients on rosiglitazone. Recent research has suggested that
rosiglitazone may also be of benefit to a subset of patients with Alzheimer's
disease not expressing the ApoE4 allele

31. N-Dealkylation of mixed tertiary
amine AndFromCyProduct
Enzyme: Cytochrome P450 1A2
BioSystem: HUMAN

32. N-Dealkylation of mixed tertiary
amine AndFromCyProduct
2,4-Thiazolidinedione ring opening
Enzyme: Cytochrome P450 1A2
BioSystem: HUMAN
Enzyme:
Cytochrome
P450 1A2
BioSystem:
HUMAN
Uses :Rosiglitazone is indicated as an adjunct to diet and exercise to improve glycemic
control in adults with type -2- diabates

33. Pioglitazone
5- (4-(2- (5-ethylpyridin – 2yl) ethoxy) Phenyl) methyl) -1,3 thiazolidine – 2,4 dione.
Pioglitazone is a thiazolidinedione used adjunctively with diet and exercise to normalize
glycemic levels in adults with type 2 diabetes mellitus.
Pioglitazone is an antihyperglycemic used as an adjunct to diet, exercise, and other
antidiabetic medications to manage type 2 diabetes mellitus.4,5,6,7 It is
administered as a racemic mixture, though there is no pharmacologic difference
between the enantiomers and they appear to interconvert in vivo with little
consequence.
The thiazolidinedione class of medications, which also includes rosiglitazone and
troglitazone, exerts its pharmacological effect primarily by promoting insulin
sensitivity and the improved uptake of blood glucose4 via agonism at the
peroxisome proliferator-activated receptor-gamma (PPARγ).1 PPARs are ligand-
activated transcription factors that are involved in the expression of more than 100
genes and affect numerous metabolic processes, most notably lipid and glucose
homeostasis

34. Metabolism
Pyridine N-oxidation
Hydroxylation of
non-terminal
aliphatic carbon
adjacent to
aromatic ring
AndFromCyProduct
Hydroxylation of
non-terminal
aliphatic carbon
adjacent to aromatic
ring
AndFromCyProduct
Enzyme: Cytochrome P450
1A2
BioSystem: HUMAN

35. Uses : Pioglitazone is indicated as an adjunct to diet and exercise to improve glycemic control
in adults with type 2 diabetes.
Adv.effects : Fluid retetntion, Congestive heart failure.
Biguanindes: The biguaninides are chemically represented by the linkage of two guanidine
group with difference in side chains. The biguanides include metformin, phen formin and
buformin.
Metformin
1- carbamimidamido – N,N – dimethyl methanimidamide.

36. MOA:
Metformin
mechanism

37. Metformin is a widely-used drug that results in clear benefits in relation to glucose
metabolism and diabetes-related complications. The mechanisms underlying these benefits
are complex and still not fully understood. Physiologically, metformin has been shown to
reduce hepatic glucose production, yet not all of its effects can be explained by this
mechanism and there is increasing evidence of a key role for the gut. At the molecular level
the findings vary depending on the doses of metformin used and duration of treatment,
with clear differences between acute and chronic administration. Metformin has been
shown to act via both AMP-activated protein kinase (AMPK)-dependent and AMPK-
independent mechanisms; by inhibition of mitochondrial respiration but also perhaps by
inhibition of mitochondrial glycerophosphate dehydrogenase, and a mechanism involving
the lysosome. In the last 10 years, we have moved from a simple picture, that metformin
improves glycaemia by acting on the liver via AMPK activation, to a much more complex
picture reflecting its multiple modes of action. More work is required to truly understand
how this drug works in its target population: individuals with type 2 diabetes.

38. MOA of metformin

39. Metabolism : Metformin is excereted in the urine via tubular excretion as un
metabolized drug with a half –life of approx 3-5 hrs.
Uses : For adjunct diet and exercise in adult patients.
Adv.effects : Epigastric discomfort, flatulence and vomiting.
Alpha –GLUCOSIDASE INHIBITORS
Alpha –amylase and alpha glucosidases are key enzymes responsible for the metabolism
of carbohydrates.
Glucosidase enzymes catalyze hydrolysis of starch to simple sugars. In humans, these
enzymes aid digestion of dietary carbohydrates and starches to produce glucose for
intestinal absorption, which in turn, leads to increase in blood glucose levels. Inhibiting the
function of these enzymes in patients with type-2 diabetes may reduce hyperglycemia.

40. Description : Oral anti-diabetic drug
Target(s) ;Glucosidase
Generic : Acarbose
Commercial Name ; Precose (United States), Glucobay (United Kingdom), Prandase
(Canada)
Combination Drug(s) : Acarbose tablets may be combined with sulfonylureas, insulin or
metformin in fixed doses (Drugs.com).
Other Synonyms : acarbosa, acarbosum
IUPAC Name ;(2S,3R,4R,5S,6R)-5-[(2R,3R,4R,5S,6R)-5-[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-
methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-en-1-yl]amino]oxan-
2-yl]oxy-3,4-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,4-triol
Ligand Code in PDB ;ACR

41. Drug-Target Complex:
Each molecule of the maltase glucoamylase (MGAM) enzyme is made up of 1867 residues
and contains two homologous catalytic subunits. The N-terminal domain (residues 1-868) is
called NtMGAM and C-terminal domain (residues 955-1867) is called CtMGAM. Both
subunits carry out the same catalytic reaction - hydrolysis of α-(1,4) linked glucose units in
linear oligosaccharide substrates yeilding glucose monomers. However, they differ in their
distinct specificity for varying lengths of malto-oligosaccharides
Both the NtMGAM and CtMGAM domains are comprised of five major sub-domains:
a trefoil Type-P domain
an N-terminal β-sandwich domain
a catalytic (β/α)8 barrel domain with two inserted loops
a proximal C-terminal domain
a distal C-terminal domain
The tertiary structures of NtMGAM and CtMGAM reveal a similar fold ,however the latter
has a 21-residue insert (shown in cyan, Figures 2b and 3b), and gives it a larger binding
pocket to bind longer substrates than NtMGAM.

43. Metabolism
Acarbose is only metabolized with in the GIT – Intestinal bacteria and also digestive
enzymes.
Glycoside hydrolysis
Alkyl-OH-glucuronidation
Alkyl-OH-
glucuronidation

44. Uses : For thr treatment and management of diabetes -II
Voglibose
Voglibose is an alpha-glucosidase inhibitor indicated in the management of postprandial
blood glucose in patients with type II diabetes.
1S,2S,3R,4S,5S – 5 –(1,3 – dihydroxy propan – 2yl) amino) -1-(hydroxymethyl) cyclohexane,
1,2,3,4 -terol

45. Mechanims of action :
Alpha-glucosidase inhibitors are saccharides that act as competitive inhibitors of enzymes
needed to digest carbohydrates: specifically alpha-glucosidase enzymes in the brush border
of the small intestines. The membrane-bound intestinal alpha-glucosidases hydrolyze
oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides
in the small intestine. Acarbose also blocks pancreatic alpha-amylase in addition to
inhibiting membrane-bound alpha-glucosidases. Pancreatic alpha-amylase hydrolyzes
complex starches to oligosaccharides in the lumen of the small intestine. Inhibition of these
enzyme systems reduces the rate of digestion of complex carbohydrates.
Maltase-glucoamylase, intestinal

46. Uses : For the treatment of diabets, especially post – prandial blood glucose.
Adv.effects : GI –Irritation, bloating, flatulence.
GLP-1 Analogs(Glucagon Like peptide -1)
Glucagon
Glucagon (shown in red) is recognized by cells using a G-protein-
coupled receptor (shown in blue). This receptor is a bit different than
a typical GPCR, like the one that recognizes adrenaline. It has an
extra domain on the outer side of the cell (shown at the top of the
illustration here), which traps glucagon and delivers it to the
membrane-spanning portion. When glucagon binds, it activates G-
proteins inside the cell, starting off a cascade of responses that lead
to release of glucose.

47. Incretineffect
the phenomenon whereby oral glucose elicits higher insulin secretory responses than does
intravenous glucose,

48. MOA of GLP-1 Agonists

49. GLP-1 is secreted from L- cells which is a part of glucose –induced insulin secretion
from pancreatic Beta cells. Metabolism of glucose in the instestinal L –cells leads
to closure of ATP- linked potassium channels resulting in the depolarization of the
membrane and entry of Ca2+ which secrete the GLP-1.
GLP-1 agonists – Exetanide, liraglutide, albiglutide.
Exetanide
GLP-I agonist

50. Amylin agonists
Amylin is a hormone that consists of a single chain of 37 amino acids and is released
from pancreatic –Beta cells, co secreted with insulin primarily involved in the
controlling post prandial blood sugars.
Pramlintide :Pramlintide is a relatively new adjunct treatment for diabetes (both type
1 and 2),
MOA :
Pramlintide is an amlyinomimetic, a functional analog of the naturally occurring
pancreatic hormone amylin. Amylin has activity in a number of gastrointestinal and
glucodynamic systems, and by mimicking its activity, pramlintide acts to improve
glycemic control through modulation of the rate of gastric emptying, prevention of
post-prandial rise in glucagon levels, and by increasing sensations of satiety, thereby
reducing caloric intake and potentiating weight loss. There appears to be at least three
distinct receptor complexes that bind with high affinity to amylin. All three complexes
contain the calcitonin receptor at the core, plus one of three Receptor activity-
modifying proteins, RAMP1, RAMP2, or RAMP3.