PR2156 Integumentary & Ocular Systems: Science & Therapeutics

[Audio] Hello students, welcome to this pre-class session that prepares you for the topic on the medicinal chemistry of glucocorticoids and antihistamines. As you know the antiinflammatory property of the glucocorticoids and the antipruritic property of the antihistamines are useful for dermatological conditions. Let's learn about how the structure of the drugs relate to their pharmacological activity and side effect..

[Audio] The following slides provide the learning outcomes for the interactive class. When you prepare for the interactive class, use these learning outcomes and the study questions to help you focus on the concepts to be learned..

[Audio] These are the learning outcomes for the segment on the medicinal chemistry of glucocorticoids..

[Audio] You will revisit concepts on pKa values, Log P and Log D that you have learned previously in PR1152. The chemistry of the antihistamines will serve as the backdrop for the application of these concepts..

[Audio] Before we start, let's take stock of the foundational chemistry topics that you have learned in PR1152 and see how these fundamental knowledge is applied in medicinal chemistry. You will now explore how medicinal chemistry is useful in pharmacy practice and hence this subject is essential component in pharmacists' education..

[Audio] This article authored by Khan et al describes the importance of medicinal chemistry in a pharmacy curriculum. You will learn about how the knowledge of medicinal chemistry can help you in your future practice. The concepts in medicinal chemistry of various pharmacological classes of drug will also help you understand new drugs belonging to the same family that may emerge in the future..

[Audio] Glucocorticoids are steroids. Now I like to spend some time to give you an introduction to the class of steroidal drugs. In the next few slides that follow, you will learn about the nomenclature, structure and conformation of steroidal compounds. I'm using Foye's Principles of Medicinal Chemistry as the recommended textbook which you can find in the medical library. The specific sections are identified for your easy reference..

[Audio] Cholesterol is a steroidal compound and it is made up of 4 rings which are functionalized with different functional groups and side chains. The steroidal nucleus comprises 4 fused rings. It is a fused carbocycle, that contains a saturated phenanthrene and a cyclopentane. The steroidal nucleus is sometimes called cyclopentanoperhydrophenanthrene. Different from steroids are the triterpenoids which is pentacyclic. It looks very similar to steroid and is often mistaken to be one by an untrained pair of eyes. The difference lies in the additional methyl groups (in red)..

[Audio] The 4 rings in steroid are labelled as rings A – D. The numbering of the carbon atoms around the rings are designated in a conventional manner. C1-10 describe a decalin, C11-17 follow rings C & D. There are 2 methyl groups that are linked to C10 and C13, these are designated as C19 and C18 respectively. These are also known as angular methyl groups. Extending from C17, there is often a side chain. The number of carbon atoms can vary. The numbering of the C atoms in the side chain is designated as shown. In our subsequent discussion on the medicinal chemistry of the glucocorticoids, this numbering system will be important as modification at different positions of the steroidal nucleus will bring about different changes to the pharmacological action..

[Audio] The steroidal structures having different number of carbon atoms are given distinct trivial names. Have a closer look at this table..

[Audio] Here are the structures of the various steroidal structures and the number of carbon atoms..

[Audio] In PR1152, you learned about the conformations of cyclohexane. The most stable conformation of the cyclohexane is the chair conformation. The hydrogens in the chair conformation of cyclohexane can adopt an axial or equatorial position. Hydrogens that are pointing above the plane of the chair conformation are known as beta hydrogens while those pointing down from the plane of the chair conformation are alpha hydrogens. These concepts will be encountered again here. To illustrate these concepts; have a look at 5a and 5b androstane. The 5a and 5b refer to the orientation of the H at position 5. With different orientation, you can see how the shape of the steroidal nucleus has changed..

[Audio] We have come to the end of the first segment on the structure, nomenclature and confirmation of steroids. Look at these questions with your teammates and see if you have grasped the different concepts..

[Audio] Cortisol is a hormone that is found naturally in our body. It is also known as hydrocortisone. Look at its structure and take note of the different functional groups present..

[Audio] Cortisone is among the first synthetic corticosteroid known. Can you spot the structural difference between cortisone and hydrocortisone?.

[Audio] Prednisone and prednisolone have improved potency compared to cortisone. This is attributed to the additional double bond in ring A. Methylprednisolone has an additional methyl group at C6 position of prednisolone..

[Audio] Fludrocortisone and betamethasone are closely related in that the latter has an additional methyl group at position 16 and a double bond at positions 1 and 2. This structural changes make betamethasone a potent glucocorticoid..

[Audio] Dexamethasone differs from triamcinolone in that the methyl group in dexamethasone is replaced by a hydroxyl group. This makes triamcinolone glucocorticoid activity equivalent to prednisolone..

[Audio] Note the positions at which esterification is introduced. The esters exhibit improved glucocorticoid activity and they may also serve as prodrugs which are activated by the body's metabolic pathways that degrade the esters. Note also the naming approach of the glucocorticoid ester..

[Audio] When two hydroxyl groups react with a ketone or an aldehyde, the corresponding products are ketal and acetal respectively. Such ketal and acetal derivatives of the glucocorticoids tend to exhibit improved activity. Review the reaction of alcohol and ketone/ aldehyde from PR1152 – this is how they are synthesized..

[Audio] This slide provides the structural features that are required for glucocorticoid's anti-inflammatory activity. Take a close look at which structures are essential for glucocorticoid activity..

[Audio] Topical glucocorticoids depends on permeation across the stratum corneum into the epidermis to exhibit the desired anti-inflammatory activity. Review the factors that influence effective permeability. Relate how the structure of the glucocorticoids provides the necessary property..

[Audio] We have come to the end of the segment on medicinal chemistry of glucocorticoids. Take a few moments to review these study questions to see if you have understood the concepts..

[Audio] For this section on the chemistry of histamine, read the sections from pg 1002-1004 in FPMC. An understanding of the physicochemical properties of histamine, the ligand that binds to the H1 histamine receptor will provide the rationale behind the design of the antihistamines..

[Audio] The physicochemical properties of histamine (which is the natural ligand of the histamine receptor) provide the basis for how the H1 antihistamines are designed. Looking at the structure of histamine, you will see the imidazole heterocycle and a primary aliphatic amine. The N atoms in imidazole and the amine contribute to the basicity of the molecule. Do you still recall what pKa values are associated with basicity strength? In the physiological pH of 7.4, how will histamine be ionized?.

[Audio] Do you remember what are tautomers? Are you able to see an amine-imine type of tautomeric pair in imidazole? Tautomerism and ionization in histamine play an important role in its binding to the receptor site. This knowledge is incorporated into the design of antagonists of the histamine receptor..

[Audio] Histamine can be viewed as a substituted ethane, with C1 having an amino group and C2 an imidazole ring. Histamine, therefore, can adopt both an anti- and gauche conformation.

[Audio] Note the strict structural requirements of histamine for H1 receptor binding, these are: Monocationic form Nt-H tautomeric form A freely rotating imidazole ring that adopts the anti-conformation which is coplanar with the side chain You can also see how histamine interacts with the binding site through various intermolecular forces.

[Audio] Have a go at finding the answers to these questions with your team mates..

[Audio] Next, let's look at 5 chemical classes of compounds that exhibit H1 antihistaminic activity. These are also known as the first generation of H1 antihistamines and they are designed based on histamine as the lead compound..

[Audio] Here are some common examples of the first generation H1 antihistamines. Can you identify the parent structure of the different chemical classes? By looking at the structure of these antihistamines, can you tell whether this molecules will be ionized at physiological environment?.

[Audio] As sedative effect is prevalent among the 1st generation of H1 antihistamines, this side effect is undesirable particularly when the antihistamines are commonly used for minor ailments such as the common cold and allergic rhinitis. How does sedation occur? Can it be avoided?.

[Audio] The 2nd generation of Hi antihistamines is known to have lesser sedative and anticholinergic properties. How are these effects reduced through structural modification?.

[Audio] Here are some examples of the non sedative H1 antihistamines. Do you expect them to be lipophilic or hydrophilic?.

[Audio] The passage taken by drug molecules across the BBB can occur in several mechanisms. These mechanism can determine the drug concentration in the CNS which can contribute to both therapeutic or side effects. There are several factors that will influence such BBB permeation..

[Audio] Passive diffusion of drug across the BBB depends on the lipophilicity of the drug molecule. Lipophilicity/ hydrophobicity of a drug molecule is expressed as its LogP or Log D value, if it has ionization group. Review the concept of Log P and see how this concept is extended to determine Log D..

[Audio] When a molecule has acidic/basic group, the extent of ionization at different pH determines the ratio of ionized and neutral molecule. This in turn affects the distribution of the molecule at that pH leading to modified LogP value. Log D value (at physiological pH) has an impact on the drug-like properties of the drug..

[Audio] The structure of the antihistamine plays an important part in its ability to cross the BBB and causing the sedative effect. Calculate the LogD value at pH 7.4 of diphenhydramine and evaluate whether it has sedative effect. In addition, review the other questions with your teammates. This marks the end of the pre-class preparation. Some of the study questions will be answered during the interactive class. Do come prepared and see if you have understood the concepts..