Lecture#5 Psoriasis Medication - Medicinal Chemistry - 2024 PDF

SAR of Psoriasis Medications (Medicinal Chemistry) PHRM 425 Hamad Alkahtani, PhD Faizah Binjubair, PhD Associate professor Assistant professor Department of Pharmaceutical Chemistry Department of Pharmaceutical...

SAR of Psoriasis Medications (Medicinal Chemistry) PHRM 425 Hamad Alkahtani, PhD Faizah Binjubair, PhD Associate professor Assistant professor Department of Pharmaceutical Chemistry Department of Pharmaceutical Chemistry College of Pharmacy, College of Pharmacy, King Saud University, King Saud University, Riyadh, KSA Riyadh, KSA 1  Objectives 1. List of different drugs used in psoriasis 2. Describe the structure-activity relationship of different psoriasis medications 3. Identify the main metabolism pathway of different psoriasis medications Dr Hamad Alkahtani, Dr Faizah Binjubair 2  Psoriasis medications Topical Systemic Corticosteroids Traditional agents Biological agents Vitamin D3 Analogs Retinoids Calcineurin Inhibitors Cyclosporine Adalimumab Acitretin Etanercept Certolizumab Methotrexate Dr Hamad Alkahtani, Dr Faizah Binjubair 3  1. Topical a. Corticosteroids Corticosteroids are the class of steroid hormones that are produced in the adrenal cortex, these drugs lower the inflammation in the body and reduce the activity of the immune system. Corticosteroids remain the first-line treatment in managing all grades of psoriasis, both as monotherapy or as a complement to systemic therapy. Corticosteroids are classified as either: Glucocorticoids (anti-inflammatory) which suppress inflammation and immunity and assist in the breakdown of fats, carbohydrates, and proteins. Mineralocorticoids (salt retaining) that regulate the balance of salt and water in the body. Dr Hamad Alkahtani, Dr Faizah Binjubair 4  1. Topical a. Corticosteroids Pharmacophore: The nucleus of all steroids is the tetracyclic C17 hydrocarbon. They are cyclopentanoperhydrophenanthrene substituted by methyl groups at C10 and C13, as well as an alkyl side-chain at C17. Structure-activity relationship: The keto (C=O) group in C3, carbonyl group in C20, and the double bond between C4 & C5 are essential for both glucocorticoids & mineralocorticoids activities. The presence of the double bond between C1 & C2 is essential for glucocorticoid activity. The presence of 11ꞵ-hydroxy is essential for glucocorticoid activity. Dr Hamad Alkahtani, Dr Faizah Binjubair 5  1. Topical a. Corticosteroids 1. Hydrocortisone (Cortisol) Glucocorticoid activity requires 11 β hydroxyl(OH) group, an α-hydroxyl group linked to C17 Metabolism: Cortisol is a 21-carbon steroid. Conversion of the 11β- hydroxyl to a ketone yields cortisone, an inactive metabolite of cortisol. It is metabolised in the liver to inactive glucuronide and sulfate metabolites. Dr Hamad Alkahtani, Dr Faizah Binjubair 6  1. Topical a. Corticosteroids 1. Hydrocortisone (Cortisol) Hormone binding to Corticosteroid-binding globulin (CBG). The CBG (blue) steroid-binding site (left). (Right schematic depiction) The interactions between CBG and cortisol. Water molecules are shown as red dots, hydrophobic interactions are shown with dashed lines, and polar interactions are shown with dotted lines. Dr Hamad Alkahtani, Dr Faizah Binjubair 7  ‫أكثر فعالية و اطول فترة من الهايدروكرتيزون‬ 1. Topical (Additional unsaturation of Ring A) 2. Prednisolone It is a glucocorticoid. Enhance anti-inflammatory effect. Metabolized more slowly than hydrocortisone. 3. Betamethasone The substitutions at C16 virtually eliminate mineralocorticoid activity. More glucocorticoid activity & anti inflammatory activity. Metabolism: It is metabolised in the liver to inactive glucuronide and sulfate metabolites. Dr Hamad Alkahtani, Dr Faizah Binjubair 8  1. Topical V Structure-activity relationship of corticosteroids (Summary) Dr Hamad Alkahtani, Dr Faizah Binjubair 9  1. Topical b. Vitamin D3 Vitamin D3, also known as cholecalciferol and its form of vitamin D. Pharmacophore: It belongs to the class of secosteroids, which are steroids with a “broken” ring, which differentiates it from typical steroids. The biologically active form of vitamin D3 is 1α,25-dihydroxyvitamin D3 (calcitriol). Structure-activity relationship: Modifications at the side-chain, A-ring, or C-ring can significantly affect its activity. The hydroxy groups at positions 1 and 25 are crucial for high-affinity binding. Dr. Hamad Alkahtani, Dr. Faizah Binjubair 10  1. Topical b. Vitamin D3 Metabolism: In the liver, calciferol is hydroxylated to calcifediol (25-hydroxycholecalciferol) by the enzyme vitamin D-25- hydroxylase. At the kidney, calcifediol subsequently serves as a substrate for 1-alpha-hydroxylase, yielding calcitriol (1,25- dihydroxycholecalciferol), the biologically active form of vitamin D3. Kidney Liver Active Dr. Hamad Alkahtani, Dr. Faizah Binjubair 11  1. Topical V c. Retinoids Retinoids are a class of chemical compounds derived from vitamin A or are chemically related to it. Pharmacophore: The core structure typically includes a polyene chain, which is a series of alternating single and double bonds, and a terminal group that can vary (e.g., retinol, retinal, retinoic acid). Three generations of retinoids have been defined, each with distinct compounds; by incorporating aromatic rings into their molecular structures for enhanced rigidity (unlike the more flexible aliphatic backbone found in vitamin A and older retinoids) these compounds reduce the potential for off-target effects. Dr. Hamad Alkahtani, Dr. Faizah Binjubair 12  1. Topical c. Retinoids Structure-activity relationship: The polyene chain and terminal group are crucial for binding affinity and specificity. Changes in the polyene chain length or terminal group, can significantly affect the binding affinity and selectivity for retinoic acid receptors (RARs), and retinoid X receptors (RXRs), thereby influencing their therapeutic effects. The presence of carboxylic acid in retinoic acid enhances its binding to RARs, while modifications in the polyene chain can affect the binding to RXRs. Metabolism: It occurs hepatically. Retinol is conjugated with glucuronic acid; the B-glucuronide undergoes enterohepatic circulation and oxidation to retinol and retinoic acid. Retinoic acid undergoes decarboxylation and conjugation with glucuronic acid. Dr. Hamad Alkahtani, Dr. Faizah Binjubair 13  1. Topical f. Calcineurin Inhibitors Calcineurin inhibitors (CNIs) are a class of immunosuppressive drugs. The two primary CNIs are cyclosporine and tacrolimus. Pharmacophore: Cyclosporine: Belongs to the class of cyclic polypeptides (used Cyclosporine systemically). Tacrolimus: Belongs to the class of macrolide lactones. Metabolism: Tacrolimus They are metabolized primarily in the liver by cytochrome P450 enzymes, particularly CYP3A4. Dr. Hamad Alkahtani, Dr. Faizah Binjubair 14  1. Topical f. Calcineurin Inhibitors Metabolism: Cyclosporine undergoes several metabolic pathways and about 25 different metabolites have been identified. Three primary metabolites are M1, M9, and M4N, which are produced from oxidation at the 1-beta, 9- gamma, and 4-N-demethylated positions, respectively. Tacrolimus is metabolized into 8 metabolites. The major metabolite identified is 13-demethyl tacrolimus. 31-O-demethyl metabolite has been reported to have the same activity as tacrolimus. Dr. Hamad Alkahtani, Dr. Faizah Binjubair 15  2. Systemic A. Traditional agents 1. Acitretin Acitretin is a second-generation retinoid. It is a metabolite of etretinate and is used primarily in the treatment of severe psoriasis orally. The presence of the carboxylic acid group is crucial for high-affinity binding 2. Methotrexate Methotrexate (MTX) belongs to the class of antimetabolites as folic acid antagonist. Methotrexate binds to dihydrofolate reductase (DHFR) with high affinity, preventing the reduction of dihydrofolate to tetrahydrofolate. Pharmacophore: Its structure includes a pteridine ring system, a para-aminobenzoic acid (PABA) moiety, and a glutamic acid residue. Dr. Hamad Alkahtani, Dr. Faizah Binjubair 16  2. Systemic A. Traditional agents 2. Methotrexate Structure-activity relationship: Replacement of glutamate tail with lipophilic agents can increase the transportation of the drug through the folate carrier system. Thiourea entity can increase the activity of the drug Tetrahydroquinazoline derivatives will affect the ligand-enzyme interaction in a positive manner, where the dibenzodiazepine ring will show the pharmacophoric features which are essential for the activity of the drug. Substitution at the 2nd, 3rd and 6th positions in the quinazolinone nucleus will inhibit the action of the drug. Substitution at ortho and para positions in the phenyl ring will decrease the tendency of the drug to bind with DHFR, thus decreasing the activity of the drug. Combining the drug with copper metal can also increase the activity of the drug. Metabolism: Methotrexate is metabolized by folylpolyglutamate synthase to methotrexate polyglutamate in the liver. 17 Dr. Hamad Alkahtani, Dr. Faizah Binjubair  2. Systemic B. Biological agents 1. Adalimumab Adalimumab belongs to the class of biologic immunosuppressants. It is specifically a TNF-α inhibitor. Adalimumab is a recombinant fully human monoclonal antibody (IgG1 type) that targets tumour necrosis factor-alpha (TNF-α). Its structure includes two heavy chains and two light chains, with each heavy chain containing a variable region and a constant region. Metabolism: Adalimumab is metabolized primarily by proteolytic degradation into small peptides and amino acids. It is not metabolized by the liver or kidneys, which reduces the risk of drug interactions. Dr. Hamad Alkahtani, Dr. Faizah Binjubair 18  2. Systemic B. Biological agents 2. Etanercept Etanercept belongs to the class of biologic immunosuppressants. It is specifically a TNF-α inhibitor. Etanercept is a fusion protein consisting of the extracellular ligand-binding portion of the human tumour necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1. Its structure allows it to bind to TNF-α molecules effectively. Metabolism: As etanercept is a fusion protein antibody, it is assumed to be metabolized via proteinases similarly to endogenous proteins. Dr. Hamad Alkahtani, Dr. Faizah Binjubair 19  2. Systemic B. Biological agents 3. Certolizumab Certolizumab belongs to the class of biologic immunosuppressants. It is specifically a TNF-α inhibitor. Certolizumab pegol (Cimzia®) is a PEGylated Fab fragment of a humanized monoclonal antibody against TNF-α. It consists of a Fab fragment linked to a polyethylene glycol (PEG) moiety, which enhances its stability and half-life. Metabolism: The presence of the PEG group in certolizumab pegol delays the metabolism and elimination of this drug. Once under metabolism, the PEG group gets cleaved from the parent compound and the antibody section is thought to be internalized cells and rescued from metabolism by recycling. The PEG section is processed normally by the action of the alcohol dehydrogenase to the 20 formation of carboxylic acid.  2. Systemic B. Biological agents Dr. Hamad Alkahtani, Dr. Faizah Binjubair 21 22