hypoglycemics medicinal chemistry

7/30/2019 Hypoglycemics Medicinal Chemistry

1/21

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


2/21

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


3/21

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


4/21

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


5/21

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.


6/21

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


7/21

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


8/21

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.


9/21

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


10/21

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


11/21

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


12/21

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


13/21

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


14/21

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.


15/21

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.


16/21

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


17/21


18/21

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


19/21

-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


20/21

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


21/21

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?

hypoglycemics medicinal chemistry

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