hypoglycemics medicinal chemistry
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Hypoglycemic AgentsGisvolds book
Insulins
Synthetic oral hypoglycemics
Top 200 Drug List
H3C
CH3
N
NH
N
H
NH
NH2
Metformin
Cl
O
O
N
H
OOO
N
H
N
H
S
CH3
GlyburideH3C N
N
O
N
H
OOO
N
H
N
H
S
Glipizide
H3C
O
H3C
N
C
O
N
H
OOO
N
H
N
H
S
Glimepiride
H3C N
NHS
O
O
O
Pioglitazone
N
CH3
NNH
S
O
O
O
Rosiglitazone
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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 disulfidelinkage (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, andB-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 removedwithout 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 slowbecause 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 andduration 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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nsu n spro, spar ,Glulisine
Insulin Lispro (Humalog): Lysine and proline
exchanged at positions B28 and B29 and theequilibrium 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 formationthatreduces the tendency to form hexamers and thus increases the
rate of absorption.
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Insulin Glulisine (Apidra):Lysine is substituted forasparagine at B3and glutamate is substituted forlysine 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:
1. Asparagine at A21 is replaced with glycine
2. 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 flatplasma level profile over 24 hours
Solution is clear but is not for intravenous use
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an nsu n nSuspension
Neutral Protamine Hagedorn (NPH) Insulin: Also called Isophane insulinsuspension. Iso means same and phane means appearance (from the
Greek). Particle size of ~ 30 m 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 2m; low concentrations of zinc used to form precipitate. Ultralente has a
particle size of ~10-40 m; 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 excessof 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 30minutes and is active about 5 to 8 hours.
Intermediate-acting, such as NPH, orlente insulin -- starts workingin 1 to 3 hours and is active 16 to 24 hours.
Long-acting, such as ultralente insulin -- starts working in 4 to 6hours, and is active 24 to 28 hours.
Insulin glargine starts working within 1 to 2 hours and continue tobe active, without peaks or dips, for about 24 hours.
A mixture of NPH and regular insulin -- starts working in 30 minutesand is active 16 to 24 hours. There are several variations with
different proportions of the mixed insulins
ummary o nsu nActivity
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Incretins and GLP-1
Incretins are a group of gastrointestinal hormonesthat 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 thatare 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 inhibitorcan be
taken orally as a tablet.
sitagliptin
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Oral Hypoglycemics
NH2H2N
NHN
NNH
H
H
H
NH
H2
N
NH
NH2
OO
H3C
CH3
NH2
N N HN
O
OS
S SNH
NH
CH3
O
O
O
H2N
Guanidine Galegine Pentamidine
Sulfaisopropylthiadiazole Carbamide
Killed patient
through severe
hypoglycemia
First sulfonylurea
to be marketed
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Sulfonylureas
R1 SHN C
HN
OO
O
R2
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
R1 and R2 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 ~ 56
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 intactpancreas.
Sulfonylureas are similar in chemistry to the sulfonamides and, thus,
potentially sharetoxicities 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. Theethylcarboxamide 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
R1 SHN C
HN
OO
O
R2
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Sulfonylurea Drugs
OOO
CN
H
N
H
S
H3C
Tolbutamide
OOO
CHN
H
N
H
S
Cl
Chlorpropamide
N
OOO
N
H
N
H
S
H3C
Tolazamide
H3C
O
OOO
N
H
N
H
S
Acetohexamide
1st 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 ofpara methyl substituent followed by oxidation to the acid
In Chlorpropamide the para chloro protects from oxidation and thus has a longerduration than tolbutamide. Also increases lipid solubility to increase potency.
Metabolism is by and -1 oxidation
Tolazamide has a cyclic substituent that makes it approximately equal to
chlorpropamide in potency even though the para substituent is the same astolbutamide. 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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Cl
O
O
N
H
OOO
N
H
N
H
S
CH3
Glyburide
H3C N
N
O
N
H
OOO
N
H
N
H
S
Glipizide
H3C
O
H3C
N
C
O
N
H
OOO
N
H
N
H
S
Glimepiride
2nd 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 3rd generation, is most potent of all
sulfonylureas. The cyclohexyl methyl is hydroxylated then oxidized to the
acid.
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S
HN
OO
H3
C N
NHS
O
O
O
Pioglitazone
THIAZOLINEDIONES
Does not increase insulin
release like the sulfonylureasbut 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 heartfailure, 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.
N
CH3
NNH
S
O
O
O
Rosiglitazone
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NH2H2N
NH H2N NH
NH2
NH NH
H3C
CH3
N
NH
N
H
NH
NH2
Metformin
NH
OH
O
OO
Cl
H3C
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
Similarmechanism of action as
the sulfonylureas without their
toxicities
BISGUANIDES
Guanidine Bisguanide
MEGLITINIDES
Meglitinide
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-Glucosidase InhibitorsHO
OHOH
H
O
HO
OHO
H3CO
HO
OHOOH
HO
O
NOH
HOHO
Acarbose
Polysaccharides are broken down to smaller saccharides
-Glucosidase breaks down more complex saccharides in the intestine suchas 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 withpostprandial 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 treatedwith 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.
NN
N
OCH3
CH3
O
O
ClCl
N
N
N
O
N
N
1
OOO
CH3NH
NH
S
H3C 2
N
OOO
NH
NH
S
H3C 3
H3C
O
OOO
NH
NH
S
4
OOO
CH3NH
NH
S
Cl 5 H3C N
N
O
NH
OOO
NH
NH
S
6Cl
O
O
NH
OOO
NH
NH
S
CH3 71. Explain fully the likely cause of the hypoglycemic crisis
2. Suggest approaches by which the type II diabetes can be controlled and the
prophylaxis of the aspergillosis continued on an outpatient basis
3. 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?
top related