Pharmaceutical Medicinal Organic Chemistry - Endocrine Drug

It maintains body functions and homeostasis by releasing hormones which are used for several body functions like growth, reproduction and defenses. Its primary use is for replacement therapy, treatment for disorders, and diagnostic purpose.

_____________________ are agents that stimulate the release of insulin from the beta cells of the pancreas.

• Agents: _________________ and _________________

Insulin secretagogues are agents that stimulate the release of insulin from the beta cells of the pancreas.

• Agents: Sulfonylureas and Meglitinides

Composed of several hormone-releasing organs

Endocrine System

____________________ usually work like hormones as a __________, semi-synthetic or _____________ compound.

• Its primary use is for replacement therapy, treatment for disorders, and diagnostic purpose.

Endocrine drugs usually work like hormones as a natural, semi-synthetic or synthetic compound.

• Its primary use is for replacement therapy, treatment for disorders, and diagnostic purpose.

Classification of Endocrine Drugs (Based on Structure)

__________ (majority) and Steroidal (adrenal cortex/____________)

Classification of Endocrine Drugs (Based on Structure)

Peptide (majority) and Steroidal (adrenal cortex/sex hormones)

True of False

Diabetes is an actual disease

False (Abnormality in your blood sugar)

What are the 3 Cardinal Signs of Diabetes

Polyuria, Polyphagia, Polydipsia

3 Cardinal Signs of Diabetes

Si patient ay ihi nang ihi

Polyuria

3 Cardinal Signs of Diabetes

Si patient ay kain nang kain

Polyphagia

3 Cardinal Signs of Diabetes

Si patient ay palaging uhaw

Polydipsia

Types of Diabetes

Insulin-dependent; has a juvenile onset, patients require insulin therapy for their lifetime

Diabetes Mellitus Type 1

Types of Diabetes

Insulin-independent; has a adult onset (commonly), patients may or may not require insulin therapy.

Diabetes Mellitus Type 2

Types of Diabetes

Glucose intolerance during pregnancy

Gestational Diabetes

Types of Diabetes

Results for non-usual causes or from other diseases present in the patient.

Secondary Diabetes Mellitus

Therapy is directed at maintaining ___________ (normal blood sugar)

Therapy is directed at maintaining euglycemic states (normal blood sugar)

__________ is a 51-amino acid protein with two chains linked by a disulfide bond. It is produced by the ________ of the pancreas.

• MOA: transports glucose into _________ and ___________ by releasing glucose transporter (GLUT 4)

• SAR:_____ and _____terminals of the amino acid Chain A and B are essential for insulin receptor binding

Insulin is a 51-amino acid protein with two chains linked by a disulfide bond. It is produced by the beta cell of the pancreas.

• MOA: transports glucose into adipose and muscle cells by releasing glucose transporter (GLUT 4)

• SAR: N- and C- terminals of the amino acid Chain A and B are essential for insulin receptor binding

Insulin is produced via ______________________ of proinsulin

Insulin is produced via proteolytic modifications of proinsulin

____________ is formed by removal 24-amino acid from _______________

Proinsulin is formed by removal 24-amino acid from preproinsulin

Classification and Pharmacokinetics of Insulin Preparation
Give the example for this type:

Rapid-acting

Lispro, Aspart, Glulisine

Classification and Pharmacokinetics of Insulin Preparation
Give the example for this type:

Short-acting

Human Insulin (Regular)

Classification and Pharmacokinetics of Insulin Preparation
Give the example for this type:

Intermediate-Acting

Lente, NPH* insulin (isophane)

Classification and Pharmacokinetics of Insulin Preparation
Give the example for this type:

Long-acting

Ultralente, Glargine, Detemir

What is the meaning of NPH?

Neutral Protamine Hagedorn

DOA of Rapid-acting

3hrs

Onset of Rapid-acting

5-10 mins

DOA of Short-acting

2-3hrs

Onset of Short-acting

30-60 mins

Numbers of crystalline zinc of Lente

2

Numbers of crystalline zinc of Ultralente

4

Name the Structure

SULFONYLUREA PHARMACOPHORE

Name the structure

MEGLITINIDE

Sulfonylureas

• MOA: binds to ___________________________________ at ATP-sensitive K-channel and opens the voltage-gated Ca-channel leading to increased intracellular Ca and ___________release of insulin.

Sulfonylureas

• MOA: binds to sulfonylurea receptor type 1 (SUR1) at ATP-sensitive K-channel and opens the voltage-gated Ca-channel leading to increased intracellular Ca and exocytotic release of insulin.

SAR of Sulfonylureas (TRUE OR FALSE)

1st Generation: small lipophilic at R1, alkyl/cyclic substituent at R2; high dose, long plasma T1/2, long DOA, low chance for ADR (hypoglycemia)

FALSE

1st Generation: small lipophilic at R1, alkyl/cyclic substituent at R2; high dose, long plasma T1/2, short DOA, high chance for ADR (hypoglycemia)

SAR of Sulfonylureas (TRUE OR FALSE)

2nd Generation: has large p-(β-arylcarboxyamidoethyl) group at R1; high potency, rapid onset, short plasma T1/2, long DOA

TRUE

Anti-Diabetic Agents (TRUE OR FALSE)

FIRST GENERATION includes Tolbutamide, Glipizide, Acetohexamide

FALSE

FIRST GENERATION includes Tolbutamide, Chlorpropramide, Acetohexamide

Name the structure

TOLBUTAMIDE

Name the structure

CHLORPROPRAMIDE

Name the structure

ACETOHEXAMIDE

Name the Structure

GLYBURIDE/GLIBENCLAMIDE

Name the structure

GLIPIZIDE

Name the structure

GLIMEPIRIDE

_____________

• MOA: similar to sulfonylureas; _____________ binds also to SUR1, SUR2A and SUR2B leading to ______________ effects.

• SAR: Meglitinide is a prototype structure — it is a __________________________of the non-sulfonylurea moiety of _______________________

Meglitinides

• MOA: similar to sulfonylureas; Repaglinide binds also to SUR1, SUR2A and SUR2B leading to extrapancreatic effects.

• SAR: Meglitinide is a prototype structure — it is a benzoic acid derivative of the non-sulfonylurea moiety of glibenclamide/glyburide

Metabolism of Meglitinides

• Repaglinide
  
  CYP ______ and 3A4 hydroxylation of piperidine ring and ________________

CYP 2C8 and 3A4 hydroxylation of piperidine ring and glucuronidation

• Nateglinide
  
  CYP 2C9 (____ %) and __________________ of isopropyl moiety

CYP 2C9 (70%) and 3A4 hydroxylation of isopropyl moiety

Name the Structure

It has rapid onset, short DOA & does not cause prolonged hyperinsulinemia

REPAGLINIDE

Name the Structure

It has rapid onset, longer DOA

NATEGLINIDE

Biguanides

• _____________________ with lifestyle change. It is highly distributed and excreted ________________ in the urine

Biguanides

• 1st line treatment with lifestyle change. It is highly distributed and excreted unchanged in the urine

Name the structure

It is the only biguanide approved for use may cause GI discomfort, lactic acidosis, metallic taste

METFORMIN

MOA of Biguanides (TRUE OR FALSE)

• increases gluconeogenesis
• decreases glycogenolysis and glycoslysis.
• decreases insulin sensitivity

FALSE

• decreases gluconeogenesis
• increases glycogenolysis and glycoslysis.
• increases insulin sensitivity

SAR of Biguanide (TRUE OR FALSE)

structure is made of 2 linked guanidine moiety.

TRUE

meaning of PPAR-Agonists

Peroxisome Proliferator Activated Receptor Agonists

Insulin Sensitizers / PPAR-Agonists

• MOA: • PPAR controls gene expression, ________ (gamma) agonist __________ glucose transporter expression leading to increasing ________________ of the body.

• ______________ gluconeogenesis and lower systematic fatty acids.

• SAR: It has a ________________ pharmacophore.

• For agonist activity: R must be a _______ substituted phenyl ring attached to the pharmacophore with a __________ bridge

Insulin Sensitizers / PPAR-Agonists

• MOA: • PPAR controls gene expression, PPARɣ (gamma) agonist increase glucose transporter expression leading to increasing insulin sensitivity of the body.

• Slows down gluconeogenesis and lower systematic fatty acids.

• SAR: It has a thiazolidinedione pharmacophore.

• For agonist activity: R must be a para- substituted phenyl ring attached to the pharmacophore with a methylene bridge

Metabolism of Insulin Sensitizers/PPAR-Agonists (TRUE OR FALSE)

CYP2C9 (most metabolites are still possess agonist activity)

TRUE

Name the structure

only available “glitazone” in the market useful for patients that cannot tolerate sulfonylurea or metformin

PIOGLITAZONE

Name the structure

not used due to severe hepatotoxicity

TROGLITAZONE

Name the structure

limited availability due to increase cardiovascular effects

ROSIGLITAZONE

Alpha-Glucosidase Inhibitors

• _________________ is an enzyme made of _________, sucrase, ___________, and glucoamylase found in the ______________.

• MOA: inhibits α-glucosidase to inhibit _______________________ which prevents absorption of mono/disaccharides leading to inhibition of ___________________________
• SAR: inhibitors mimic the __________________ of α-glucosidase by having similar structures.

Alpha-Glucosidase Inhibitors

• α-glucosidase is an enzyme made of maltase, sucrase, isomaltase, and glucoamylase found in the small intestine.

• MOA: inhibits α-glucosidase to inhibit carbohydrate breakdown which prevents absorption of mono/disaccharides leading to inhibition of post-prandial hyperglycemia.
• SAR: inhibitors mimic the natural substrates of α-glucosidase by having similar structures.

Name the structure

extremely low oral bioavailability

ACARBOSE

Name the structure

poorly absorbed

VOGLIBOSE

Name the structure

absorbed orally, not metabolized excreted unchanged

MIGLITOL

It aids in mimicking natural disaccharide substrate

POLYHYDROXY Groups

Glucagon-like Peptide-1 (GLP-1) Agonist

• GLP-1 is a __________ amino acid peptide produced by prohormone convertase enzymes from __________________. It is indicated for additional therapy with ______________ or metformin to reach HbA1c <___%

• MOA: GLP-1 is released from _________ of GIT in response to ________. GLP-1 promotes __________ secretion from pancreas.

• SAR: GLP-1 agonist analogs have _______________ amino acid modification to resist metabolism by _____________________

Glucagon-like Peptide-1 (GLP-1) Agonist

• GLP-1 is a 30-31 amino acid peptide produced by prohormone convertase enzymes from proglucagon. It is indicated for additional therapy with sulfonylurea or metformin to reach HbA1c <7%

• MOA: GLP-1 is released from L-cells of GIT in response to food. GLP-1 promotes insulin secretion from pancreas.

• SAR: GLP-1 agonist analogs have penultimate amino acid modification to resist metabolism by Dipeptidyl peptidase IV (DPP-IV)

4 Agents of GLP-1 Agonist

Exenatide, Liraglutide, Albiglutide, Dulaglutide

Dipeptidyl Peptidase IV Inhibitors (DPP IV Inhibitors)

• MOA: binds to the _____________ site in DPP-IV, alternatives to GLP-1 agonist analogs

• SAR: It has 3 pharmacophore structure: ________________________, ______________, and pyrimidine-2,4-dione.

• The ____________ binds to the active serine site in DPP-IV.
• It can be taken alone or with _______________ or _______________; it rarely causes hypoglycemia.

Dipeptidyl Peptidase IV Inhibitors (DPP IV Inhibitors)

• MOA: binds to the active serine site in DPP-IV, alternatives to GLP-1 agonist analogs

• SAR: It has 3 pharmacophore structure: 𝛼-aminoacylpyrrolidine, xanthine, and pyrimidine-2,4-dione.

• The cyano group binds to the active serine site in DPP-IV.
• It can be taken alone or with metformin or thiazolidinedione; it rarely causes hypoglycemia.

Name the structure

has piperazine fused pyrazole with α-aminoacyl moiety (most popular drug)

SITAGLIPTIN

Name the structure

pyrimidine-2,4-dione pharmacophore

ALOGLIPTIN

Name the structure

α-aminoacylpyrrolidine pharmacophore

SAXAGLIPTIN

Name the structure

α-aminoacylpyrrolidine pharmacophore

VILDAGLIPTIN

Name the
structure

xanthine pharmacophore

LINAGLIPTIN

Amylin Agonist

• Amylin is a ____-amino acid hormone released with ________.

• MOA: suppress ___________________ , delaying ______________________, to modulate appetite centers which aids in maintaining glucose plasma level.

• SAR: _______________ is an amylin agonist analog.
• Proline replacement for _______, Ser28, Ser29

Amylin Agonist

• Amylin is a 37-amino acid hormone released with insulin.

• MOA: suppress glucagon secretion, delaying gastric emptying time, to modulate appetite centers which aids in maintaining glucose plasma level.

• SAR: Pramlintide is an amylin agonist analog.
• Proline replacement for Ala25, Ser28, Ser29

It cannot be given to patient with renal impairment

Sodium Glucose Cotransporter (SGLT2) Inhibitor

Sodium Glucose Cotransporter (SGLT2) Inhibitor

• SGLT2 aids in ______________ of glucose from ________________________

• MOA: inhibit SGLT2 leading to ______________ renal threshold for glucose which results to ____________ urinary glucose excretion.

• SAR: It has a ____________________________ and a glucose moiety that binds to __________ and ___________ moiety of the transporter.

• Not recommended for ________ diabetes and patients with __________________

Sodium Glucose Cotransporter (SGLT2) Inhibitor

• SGLT2 aids in reabsorption of glucose from renal proximal tubules

• MOA: inhibit SGLT2 leading to decreased renal threshold for glucose which results to increased urinary glucose excretion.

• SAR: It has a phlorizin pharmacophore and a glucose moiety that binds to Thr156 and Lys157 moiety of the transporter.

• Not recommended for Type 1 diabetes and patients with renal impairment.

Name the structure

pharmacophore w/glucose

PHLORIZIN

Name the structure

most commonly prescribed

DAPAGLIFLOZIN

Name the structure

most commonly prescribed

CANAGLIFLOZIN

Name the structure

EMPAGLIFLOZIN

It is the only mamalian organ that can incorporate iodine into organic molecule

Thyroid gland

Formation of thyroid hormone

Organification

Thyroid gland is the only mamalian organ that can incorporate iodine into organic molecule and is the source of _____________and _____________________.

• These hormones are needed for__________________________ and adult metabolism.

• Disorders associated to thyroid gland function are usually due to _______________ (hyper-) or ______________ (hypo-) that is diagnosed through levels of TSH, ____ and ____.

• Medications are _________________________________________ and/or antithyroid drugs

Thyroid gland is the only mamalian organ that can incorporate iodine into organic molecule and is the source of thyroxine (T4) and triiodothyronine (T3).

• These hormones are needed for fetal development and adult metabolism.

• Disorders associated to thyroid gland function are usually due to overactivity (hyper-) or underactivity (hypo-) that is diagnosed through levels of TSH, T3 and T4.

• Medications are hormone replacement therapy and/or antithyroid drugs

Name the structure

THYROXINE

Name the structure

3,5,3’-Triiodothyronine (T3) - Activated

Name the structure

3,3’ ,5’-Triiodothyronine (T3) - Inactivated

(HYPOTHYROIDISM/HYPERTHYROIDISM)

Bradycardia, reduced cardiac output

HYPOTHYROIDISM (CV)

(HYPOTHYROIDISM/HYPERTHYROIDISM)

Stiffness, decreased deep tendon reflex

HYPOTHYROIDISM (Musculoskeletal)

(HYPOTHYROIDISM/HYPERTHYROIDISM)

Nervousness, tremor

HYPERTHYROIDISM (CNS)

(HYPOTHYROIDISM/HYPERTHYROIDISM)

Pleural effusions, hypoventilation

HYPOTHYROIDISM (Respiratory)

(HYPOTHYROIDISM/HYPERTHYROIDISM)

Warm, moist skin (more secretions), Plummer’s nails, pretibial dermopathy

HYPERTHYROIDISM (Integumentary)

(HYPOTHYROIDISM/HYPERTHYROIDISM)

Dyspnea

HYPERTHYROIDISM (Respiratory)

(HYPOTHYROIDISM/HYPERTHYROIDISM)

Tachycardia (most prominent), increased cardiac output

HYPERTHYROIDISM (CV)

(HYPOTHYROIDISM/HYPERTHYROIDISM)

Pale, cool skin (reduced secretions), brittle hair and nails

HYPOTHYROIDISM (Integumentary)

(HYPOTHYROIDISM/HYPERTHYROIDISM)

Normochromic anemia

Both

(HYPOTHYROIDISM/HYPERTHYROIDISM)

Infertility, decreased libido, impotence, oligospermia

HYPOTHYROIDISM (Reproductive)

(HYPOTHYROIDISM/HYPERTHYROIDISM)

Weakness, increased deep tendon reflex

HYPERTHYROIDISM (Musculoskeletal)

(HYPOTHYROIDISM/HYPERTHYROIDISM)

Polyuria, increased renal blood flow

HYPERTHYROIDISM (Renal)

(HYPOTHYROIDISM/HYPERTHYROIDISM)

Reduced appetite

HYPOTHYROIDISM ( GIT)

(HYPOTHYROIDISM/HYPERTHYROIDISM)

Weight gain (reduced metabolism)

HYPOTHYROIDISM (Metabolism)

(HYPOTHYROIDISM/HYPERTHYROIDISM)

Retraction of upper eyelid Exophthalmos (protrusion of eyeball)

HYPERTHYROIDISM (Face)

(HYPOTHYROIDISM/HYPERTHYROIDISM)

Impaired water excretion, decreased renal blood flow

HYPOTHYROIDISM (Renal)

(HYPOTHYROIDISM/HYPERTHYROIDISM)

Drooping of eyelids, puffy face, large tongue

HYPOTHYROIDISM (Face)

(HYPOTHYROIDISM/HYPERTHYROIDISM)

Weight loss (increased metabolism)

HYPERTHYROIDISM (Metabolism)

(HYPOTHYROIDISM/HYPERTHYROIDISM)

Lethargy, slowing of mental processes

HYPOTHYROIDISM (CNS)