Medicinal Chemistry of Drugs Affecting Cardiovascular and Endocrine Systems

This chapter presents a comprehensive account of the medicinal chemistry of drugs affecting the renin-angiotensin system (RAS). It provides the mechanism of drug action and details structure-activity relationships (SAR) of the drugs affecting RAS to give the knowledge base for pharmacists. After studying this chapter, students will be able to:

• Describe the historical background the RAS and drugs acting on this system.

• Explain RAS enzymes and hormones and their roles in blood pressure.

• Classify drugs acting on the RAS and their structures and binding.

• Discuss in detail the chemistry and SAR of the antagonists involved in RAS including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) and renin inhibitors.

• Delineate the clinical significance and therapeutic evaluations of these classes of drugs by solving case studies.

• Explain the discovery process of ACEIs and ARBs.

This chapter is a comprehensive account of the medicinal chemistry of antihypertensive drugs, Ca2+-channel blockers (CCBs). It provides the mechanism of drug action and detailed structure-activity relationships (SAR) of the CCBs to give the knowledge base for pharmacists. After studying this chapter, students will be able to:

 • Comprehend the historical background of the CCBs.

 • Classify different types of voltage-gated Ca2+ channels (VGCCs) and their clinical significance.

• Explain CCBs and their clinical significance.

• Describe the mechanisms of action of CCBs at the molecular level including their binding modes against the VGCCs.

• Describe the SAR of the different classes of CCBs.

• Delineate clinical significance and therapeutic evaluations of these classes of drugs by solving case studies.

• Articulate the discovery process of a few CCBs.

This chapter is a comprehensive account of the medicinal chemistry of diuretic agents. It provides the mechanism of drug action and details the structure activity relationships (SAR) of these drugs to provide a knowledge base for pharmacists. After studying this chapter, students will be able to:

• Identify the chemical classification to which a diuretic agent or therapeutic belongs based on drug structure.

• Evaluate the chemical principles of different classes of diuretics.

• Compare and contrast the potency, onset, and duration of action of the diuretic agents.

• Identify chemical metabolites of the diuretics that increase the risk of nephron and hepatotoxicity.

• Select an appropriate diuretic agent based on patient-specific symptoms of hypertension or other problems.

• Rationalize the clinical application of all diuretic drug classes.

• Communicate the chemical rationale for a diuretic to health professionals.

• Delineate the clinical significance and therapeutic evaluations of these classes of drugs by solving case studies.

 • Identify the discovery process of selected diuretic agents.

This chapter is a comprehensive account of the medicinal chemistry of anticoagulants, antiplatelets and thrombolytic agents and related drugs. It provides the mechanism of drug action and detailed structure-activity relationship (SAR) of the drugs affecting in these clinical areas to give the knowledge base for pharmacists. After studying this chapter, students will be able to:

• Describe the historical background of the anticoagulants, antiplatelets and thrombolytic agents and and related drugs.

• Describe the mechanism of action, pharmacokinetics (PK), and adverse drug reaction (ADR) of the anticoagulants, antiplatelets and thrombolytic agents.

• Explain the physiology and pathophysiology of clotting cascades and identify the components of a blood clot. • Classify major anticoagulant drugs and their structures and binding.

• Discuss in detail the chemistry and SAR of these drugs.

• Distinguish among drugs used as antiplatelets, anticoagulants and fibrinolytic agents.

 • Delineate the clinical significance and therapeutic evaluations of these classes of drugs by solving case studies.

• Explain the discovery process of a few specific drugs in these classes. 

This chapter is a comprehensive account of the medicinal chemistry of antihistamines, H2 receptor (H2R) blockers, H3 receptor (H3R) blockers, and proton pump inhibitors (PPIs). It provides the mechanism of drug action and detailed structure-activity relationship (SAR) of the drugs in these classes to give the knowledge base for pharmacists. After studying this chapter, students will be able to:

 • Describe the physiochemical properties of histamine and histamine receptors.

• Identify chemical classifications and describe the SAR of antihistamines, H2R and H3R antagonists.

• Differentiate receptor binding patterns and structural features between histamine receptor agonists and antagonists.

• Distinguish between sedating and non-sedating antihistamines, as well as the first-, second- and third-generation antihistamines.

• Describe the structural features of cromolyn and related mast cell stabilizers and their therapeutic applications.

• Discuss the proton pump inhibitors, including their development, mechanism of action, and structural and physicochemical features.

• Apply the medicinal chemistry principles to the clinically relevant case studies.

• Explain the drug discovery story of representative drugs of different classes. 

This chapter is a comprehensive account of diabetes and the medicinal chemistry of antidiabetic drugs. It provides the mechanism of disease progression and drug action and detailed structure-activity relationships (SAR) of antidiabetic drugs to give the knowledge base for pharmacists. After studying this chapter, students will be able to:

• Discuss the epidemiology and etiology of diabetes.

• Describe the clinical features of diabetes and differentiate between type I and type II diabetes.

• Discuss various risk factors and corresponding mechanisms responsible for the development of diabetes.

 • Review biosynthesis of insulin, its metabolic outcomes, regulation of insulin secretion, and insulin signaling.

 • Explain in detail the pathophysiologic mechanisms responsible for the clinical features of diabetes.

• Evaluate the clinical role of natural human insulin and commercially available other insulin products and discuss its mechanism of action, pharmacokinetics, adverse effects, motor complications, drug interactions, contraindications, and precautions.

• Discuss the mechanism of action, pharmacokinetics, adverse effects, motor complications, drug interactions, contraindications, and precautions for each class of antidiabetic drugs listed below.

o Sulfonylureas: tolbutamide (Orinase® ), tolazamide (Tolinase® ), chlorpropamide (Diabinese® ), and acetohexamide (Dymelor® ), glyburide (Diabeta® ), glipizide (Glucotrol® ), and glimepiride (Amaryl® ).

o Meglitinides: repaglinide (Prandin® ), nateglinide (Starlix® ).

o Biguanides: metformin (Glucophage® , Glucophage XR).

o Peroxisome proliferator activated receptor (PPAR) agonists/Thiazolidinediones: pioglitazone (Actos® ), rosiglitazone (Avandia® ).

 o Alpha glucosidase inhibitors: acarbose (Precose® ).

o Glucagon-like peptide-1 (GLP-1) agonists: dulaglutide (Trulicity® ), exenatide (Bydureon® , Byetta® ), liraglutide (Victoza® ), lixisenatide (Adlyxin® ), semalgutide (Ozempic® , Rybelsus® ).

o Dipeptidyl peptidase-4 (DPP-4) inhibitors: alogliptin (Nesina® ), linagliptin (Tradjenta® ), saxagliptin (Onglyza® ), sitagliptin (Januvia® ).

 o Amylin agonist: pramlintide (Symlin® ).

 o Sodium-glucose cotransporter-2 (SGLT2) inhibitors: empagliflozin (Jardiance® ), canagliflozin (Invokana® ), dapagliflozin (Farxiga® ), ertugliflozin (Steglatro® ).

o Miscellaneous agents.

Treatments that involve the use of hormones or their antagonists are commonly referred to as hormone therapy or hormonal therapy. Oncologic hormone therapy, hormone replacement therapy (HRT), androgen replacement therapy (ART), oral contraceptive pills and gender-affirming hormone therapy are the major classes of hormonal therapy in addition to a few others. Some hormonal therapies will be discussed in detail under different chapters including oncologic hormone therapy, glucocorticoids and mineralocorticoids and insulin under antineoplastic agents, antiinflammatory steroids and antidiabetic agents, respectively. After studying this chapter, students will be able to:

• Define and classify hormonal therapy and differentiate between hormonal therapy and treatment.

• Explain all types of hormone replacement therapy including menopausal, androgens, and oral contraceptives.

 • Discuss the use of androgen replacement therapy (ART) in males with low levels of testosterone due to disease or aging.

• Describe gender-affirming hormone therapy such as feminizing hormone therapy and masculinizing hormone therapy. • Identify appropriate growth hormone therapy for growth hormone deficiency.

• Demonstrate understanding of thyroid hormone replacement in hypothyroidism and antithyroid therapy in hyperthyroidism.

• Demonstrate clear guidance to the use of oral contraceptive pills for various purposes including birth control. 

This chapter is a comprehensive account of the medicinal chemistry of drugs arising from structural modifications of prostanoids, which are naturally occurring eicosanoids. These drugs are used for a variety of diseases including but not limited to glaucoma, pulmonary arterial hypertension, and peptic ulcers. This chapter provides the mechanism of drug action and structure-activity relationships (SAR) of these drugs. After studying this chapter, students will be able to:

• Describe the historical background of prostanoids as clinical agents.

• Explain the structure, functions, classifications and biosynthesis of eicosanoids.

• Discuss in detail the chemistry and SAR of the prostanoids involved in the treatment of glaucoma, pulmonary arterial hypertension, peptic ulcer, and other diseases.

 • Delineate the clinical significance and therapeutic evaluations of these classes of drugs by solving case studies.

• Explain the discovery process of latanoprost and zafirlukast.