Diabetes-2 MEDCHEM

what are sulfonylureas?

• para substituted benzenesulfonylurea derivatives

• weak acids and classified into first- and second-generations

what is the pharmacophore of sunfonylureas?

benzenesulfonylurea

what do first-generation sulfonylureas contain?

• small lipophilic substituent on the position of the phenyl ring (R1 of the pharmacophore)

• lipophilic alkyl or cycloalkyl substituent on the non- sulfonyl-attached urea nitrogen (R2 of the pharmacophore)

are first or second-generation sulfonylureas more potent?

The second-generation sulfonylureas are more potent (50-100 times more active than first generation), with more rapid onset, shorter plasma half-lives, and longer durations of action

what is the enhancement of activity of second-generation sulfonylureas due to?

strong binding affinity to the ATPsensitive K+ channel associated with the larger p-(b-arylcarboxyamidoethyl) group which replaces the small lipophilic p-substituents found in the first-generation agents

what do sulfonylureas stimulate the release of?

insulin from the pancreatic b-cells

where are the binding residues for Glyburide?

in the sulfonylurea receptor subunits (SUR1) subdomain

what is the binding residues for Glyburide in the sulfonylurea receptor subunits (SUR1) subdomain is attributed to?

the strong binding affinity of the p-( b-arylcarboxyamidoethyl) group (in red) to Asn1245 and Tyr1242

where and how is Glimepiride metabolized?

metabolized in the liver, primarily by CYP2C9

what is Glimepiride metabolized to?

the active metabolite M-1

what is the active metabolite M-1 of Glimepiride further metabolized to?

the inactive metabolite M-2

how is the M1 metabolite of Glimepiride metabolized to M2?

metabolized by cytosolic dehydrogenases

Are biguanides acidic or basic?

basic

how are biguanides represented?

by the linkage of two guanidine groups with different side chains

how do biguanides work?

reduces hepatic glucose production by decreasing gluconeogenesis and stimulating glycolysis and by enhancing insulin sensitivity

can biguanides cause hypoglycemia?

no, they do not directly affect insulin secretion

do biguanides induce weight gain?

no

what are important actions biguanides possess that help in treating cardiovascular complications?

• antihypertriglyceridemic effects

• vasoprotective properties

what is the only biguanide?

Metformin (Glucophage)

what is the first line treatment for T2DM?

Metformin

what can high doses of metformin result in? who is not recommended to take this?

• can increase lactic acidosis

• not recommended for type 2 diabetic patients who are inclined toward metabolic ketoacidosis

what are Peroxisome Proliferator Activated Receptor (PPAR) Agonists?

central regulators of lipid and carbohydrate metabolism and inflammatory pathways and help maintain homeostasis

(insulin sensitizers)

what group do PPAR agonists belong to?

the nuclear hormone receptor superfamily of ligand-activated transcription factors and are closely related to steroid, retinoid, and thyroid hormone receptors

the PPAR receptor family is comprised of what three members?

PPAR α, β, and γ

what PPAR receptor is expressed in adipose tissue, where it helps control lipid differentiation?

PPAR γ

what are classic examples of PPAR γ agonists?

thiazolidenediones (TZD) and are commonly referred to as the "glitazones."

what is the MOA of glitazones?

Linoleic acid and thiazolidinedione PPAR γ agonists (glitazones) act by increasing the sensitivity of cells to insulin

what do the glitazones also decrease?

both systemic fatty acid production and fatty acid uptake, which contributes to increased sensitization of cells to insulin

what does activation of PPAR γ result in?

improves glucose uptake by skeletal muscle and reduces glucose production by slowing gluconeogenesis

what is responsible for the activity of glitazones?

thiazolidinedione moiety

what is essential for the activity of glitazones?

A phenyl ring attached to the thiazolidinedione ring via a methylene group

is the saturated or unsaturated linker of glitazones more potent?

saturated linker is found to be more potent than the unsaturated counterpart

How is pioglitazone metabolized?

Oxidation at either carbon adjacent to the pyridine ring leads to M-1, M-2, and M-3 metabolites

what do the M-1, M-2, and M-3 metabolites of pioglitazone contribute to?

the biological activity of Pioglitazone

what are key enzymes responsible for the metabolism of carbohydrates?

α-Amylase and α-glucosidase

what is responsible for the breakdown of complex polysaccharides into oligo- and disaccharides, preparing them for intestinal absorption?

The salivary and pancreatic α-amylases

what does α-Glucosidase consist of?

maltase, sucrase, isomaltase, and glucoamylase

what is α-Glucosidase?

is a membrane-bound enzyme present in the brush border of the small intestine and is in relatively high concentrations in the proximal part of the jejunum

what enzyme catalyzes the conversion of the disaccharides' sucrose and maltose into glucose?

α-Glucosidase

--> The resulting monosaccharides are then absorbed by the enterocytes of the jejunum and enter systemic circulation, as well as various biochemical pathways for the production of energy

what does inhibition of α-Glucosidase result in?

• a delay carbohydrate absorption in the gut by moving undigested disaccharides into the distal sections of the small intestine and colon

• The result is the prevention of glucose production, thereby reducing postprandial hyperglycemia

what defines hyperglycemia?

a plasma glucose level >7.8 mmol/L (140 mg/dL) 1-2 hours after ingestion of food

where do all α-glucosidase inhibitors act? what are the excreted as?

act locally and are excreted unchanged in the feces, obviating metabolic drug interactions

what is acarbose?

• an oligosaccharide and is the drug of choice in competitive inhibitors of the a-glucosidase enzyme

• has a high affinity for sucrase

• has a lesser affinity for glucoamylase and pancreatic a-amylase in humans

does acarbose pose a risk of hypoglycemia and weight gain?

no

what are Voglibose and Miglitol?

they are other a-glucosidase inhibitors in clinical use for the management of diabetes

what are a-Glucosidase inhibitors frequently used in combo therapy with?

sulfonylureas

what is glucagon-like peptide-1 (GLP-1)?

is an endogenous incretin and plays a significant role in glucose homeostasis

GLP-1 is a ____ amino acid containing peptide secreted from intestinal L-cells in response to food intake.

30

how is GLP-1 produced?

post-translational processing of preproglucagon, a precursor of many glucagon related peptides

what two forms does GLP-1 exist in?

two equipotent forms, GLP-1(7-36)-NH2 and GLP-1(7-37), the former being more abundant

what does GLP-1 bind to?

binds to and activates the GLP-1 receptor (GLP-1R) belonging to class B family of G-protein-coupled receptors (GPCRs) in order to exert its regulatory functions

what does metabolism of glucose in the intestinal L-cells lead to?

closure of ATP-linked K+ channels resulting in depolarization of the membrane and entry of Ca++ that leads to the secretion of GLP-1

where is the GLP-1 receptor located?

on the pancreatic b-cells and, after binding, stimulates insulin secretion

what is the half-life of GLP-1?

1-2 minutes

what is GLP-1 metabolized by?

rapidly metabolized by an aminopeptidase enzyme which is called Dipeptidyl Peptidase-IV (DPP-IV), yielding an inactive peptide that is two amino acids shorter

why is GLP-1 is so susceptible to DPP-IV?

because it contains an Ala in the penultimate N-terminal position (at position 8)

Substitution at the Ala position of GLP-1 with what AA gives analogues that are more stable in vitro than GLP-1 (t1/ 2 = 28 min) under the same conditions?

• Thr (t1/ 2 = 197 min)

• Gly (t1/ 2 = 159 min)

• Ser (t1/ 2 = 174 min)

• a-aminoisobutyric acid (AiB)

which analogue is almost twice as potent as GLP-1?

AiB analogue

what is exenatide?

a 39-amino acid peptide analogue of GLP-1 (7-36)

what GLP-1 receptor agonist is resistant to the action of DPP-IV?

exenatide

where is the modification to form exenatide from GLP-1?

Modification occurred at the 8th position with Gly instead of Ala in the penultimate N-terminal position

exenatide is _____ homologous to human GLP-1 and has an in vivo half-life of approximately 3 hours

53%

what is Liraglutide?

• an acylated GLP-1 (7-37) derivative

• It is the C16 derivative a-l-glutamoyl- ( N-a-hexadecanoyl)-Lys26 Arg34-GLP-1.

what has the best combination of albumin binding to retard renal elimination?

Liraglutide

why does Liraglutide have the best combination of albumin binding to retard renal elimination?

because of the fatty acid-side chain and DPP-IV degradation resistance because of the replacement of Lys34 with Arg34

what are the effects of Liraglutide?

• reduction of hyperglycemia

• including suppression of inappropriate glucagon secretion,

• slowing of gastric emptying

• enhancement of b-cell function and mass

why does Liraglutide have a black box warning?

because of a possible link to the production of thyroid C-cell tumors

only use in patients where benefits > risks

what is Dulaglutide?

(GLP-1 immunoglobulin G (IgG4) Fc fusion protein with extended activity) is a fusion protein

how is Dulaglutide prepared?

by fusing two identical GLP-1 (7-37) analogues (Gly8, Glu22, Gly36) to a modified IgG4 Fc fragment

• thereby protecting the GLP-1 moiety from inactivation by DPP-IV (Confer DPP-IV resistance).

what is the linker used in the formation of Dulaglutide?

a small peptide joined to the dimer via disulfide bonds

what is the significance of the IgG4 moiety of Dulaglutide?

acts to decrease both renal clearance and antigen-antibody formation.

Dulaglutide has ∼ ____% amino acid homogeneity to human GLP-1.

90

describe the administration of Dulaglutide:

• administered SC and is slowly absorbed

• administered on a weekly basis

• has a half-life of ∼ 5 days (long circulating half-life)

what is Lixisenitide?

a modified version of Exenatide, with one amino acid deleted (Pro38) and a string of six Lys residues added to the Ser at the carboxylic acid terminus

--> This modification extends the half-life to about 2-5 hrs, allows for once to twice daily SC administration

why do patients develop antibodies against this Lixisenitide (50%-60%), and severe hypersensitivity reactions have been observed?

because it has only about 50% amino acid homology to human GLP-1 (7-37)

what is Semaglutide (Ozempic)?

a long-acting human GLP-1 analogue ([ Aib8, Arg34]-hGLP-1)

why does Semaglutide have resistance to DPP IV degradation?

bc the amino-terminal sequence substitutes Ala8 for a-aminoisobutyric acid (AiB)

how is Lys26 is derivatized in semaglutide?

with a C18 fatty diacid using an 8-amino-3,6- dioxooctanoic acid (ADO) linker bridged via a glutamic acid moiety

Semaglutide has a ___% amino acid homology to hGLP-1.

94

does the fatty acid side chain of Semaglutide or Liraglutide have a higher affinity for albumin?

• Semaglutide has an affinity that is 3-fold greater

• Therefore, Semaglutide exhibits an extremely long half-life of ∼ 165 hours enabling once weekly SC dosing

what is the dual GLP-1/GIP Receptor Agonist?

Tirzepatide

what is Tirzepatide?

• linear polypeptide of 39 AA

• an analog of the human GIP hormone with a C20 fatty-diacid portion attached, used to optimize the uptake and metabolism of the compound

what is the fatty-diacid section (eicosanedioic acid) of Tirzepatide linked?

via a glutamic acid and two (2-(2- aminoethoxy)ethoxy)acetic acid units to the side chain of the lysine residue

--> This arrangement allows for a much longer half-life, extending the time between doses, because of its high affinity to albumin thus permits convenient once-weekly dosing

does Tirzepatide have a greater affinity to GIP receptors or GLP-1 receptors?

greater affinity to GIP

what does the dual agonist behavior of Tirzepatide have been shown to produce?

a greater reduction of hyperglycemia compared to a selective GLP-1 receptor agonist

what is the major problem with GLP-1 analogues?

• their need for SC administration, which may limit patient compliance

• they are peptide drugs that have the potential to be immunogenic.

how is GLP-1 deactivated?

by Dipeptidyl Peptidase-IV (DPP-IV), a serine protease, which removes a dipeptide from the N-terminus

what are the DPP-IV inhibitors in current use for the treatment of diabetic type-2?

Sitagliptin, Vildagliptin, Saxagliptin, Linaglitin, and Alogliptin

what are DPP-IV inhibitors peptide derivatives of?

a-aminoacylpyrrolidines or a-aminoacylthiazolidines, which also take advantage of the enzyme's high preference for Pro binding

where do DPP-IV have an electrophilic group?

in the 2-position of the pyrrolidine or thiazolidine ring

where is cyano the most common group present in?

Vildagliptin, Saxagliptin, and Alogliptin.

DPP-IV have basic amino group in the position equivalent to the penultimate amino acid (Ala) in GLP-1 which also is important for?

binding through ionic interaction with Glu205 and Glu206 of DDP-IV

where do all DPP-IV inhibitors bind?

inside a hydrophobic pocket of DDP-IV made up of Arg125, Glu205, Glu206, Tyr547, Tyr662, Tyr666, Ser630, and Phe357

Saxagliptin and Vildagliptin have __________________________ pharmacophore

a-aminoacylpyrrolidine

what does Sitagliptin contain in place of the pyrorolidine ring?

has a piperazine ring fused to a pyrazole

--> making it a triazole ring and contains the b-amino acyl moiety and the amide bond

Linagliptin contains a _______________ as the central pharmacophore.

xanthine ring

Alogliptin contains the _____________ pharmacophore with the essential amino group on the piperidine ring.

2,4-pyrimidinedione

what is the cyano group od Saxagliptin, Vildagliptin, and Alogliptin important for?

it forms a reversible covalent amidate with the enzyme Ser630, resulting in the deactivation of DPP-IV.

what does the The xanthine pharmacophore of Linagliptin contain?

a C8 aminopiperidine and an N7 butynyl substituent for binding to the DPP-IV catalytic site

what does the aminopiperidine's primary amino group of Linagliptin occupy?

the recognition site for the amino terminus of GLP-1, and hydrogen and ionic bonds with Glu residues