Medicinal Chemistry II Lecture Notes PDF

Faculty Of Pharmacy, Alexandria University Medicinal Chemistry. II Prof. Dr. Mona El Semary 1 If you can DREAM IT You can DO IT 2  After completing this lecture, the student should be able to: 1. Understand the general structur...

Faculty Of Pharmacy, Alexandria University Medicinal Chemistry. II Prof. Dr. Mona El Semary 1 If you can DREAM IT You can DO IT 2  After completing this lecture, the student should be able to: 1. Understand the general structure of the steroidal molecules 2. Define, classify and give the appropriate nomenclature of different steroidal molecules 3. Understand Structure, stereochemistry and nomenclature of the steroid backbone 4. Discuss the factors affecting physicochemical properties of the drug 5. Predict different properties of the steroidal molecule, and the different modes of administration 6. Understand the different medicinal uses and side effects of each class. 7. Understand the difference in structures between the agonist and antagonotic activity of each class 8. Apprehend and apply the prodrug concept DR.Mona El Semary 3 Steroids, Steroidal Hormones and Related Drugs Steroids are a unique class of chemical compounds that are found throughout the animal and plant kingdom. This class of compounds includes: sterols bile acids and steroidal hormones. Steroidal hormones and related products represent one of the most widely used classes of therapeutic agents. 4  These drugs are used primarily in o birth control o hormone-replacement therapy (HRT) inflammatory conditions o and cancer treatment. Most of these agents are chemically based on a common structural backbone, the steroid backbone. 5  The basic structure of this group of compounds belongs to a hydrocarbon skeleton composed of four fused rings. phenanthrene cyclopentanoperhydrophenanthrene The parent compound of all the steroids is cholesterol i.e they are all biosynthesized from cholesterol which in turn is synthesized from acetyl-CoA 6 Structure, stereochemistry and nomenclature of the steroid backbone The steroid backbone composed of four fused rings, 3 cyclohexane rings, A, B and C rings (perhydrophenanthrene) and one cyclopentane ring, D. 7  The numbering system is unique to the steroidal nucleus, groups that exist above the plane of the molecule are referred to as in the -position, and hose below the plane are in the -position. 8  The stereochemistry of the ring fusion of the steroidal backbone dictates the overall shape of the molecule and consequently the biological effect of the compound. The simplest member of the steroidal compounds is the 17-carbons structure Gonane. 9  According to the fusion of the rings A and B, Gonane can exist in either the -form or the - form most of the human steroidal hormones and related drugs are derived from the -Gonane structure. Note that in the -Gonane rings A and B are trans- fused and the hydrogen on carbon number 5 is in the -side, hence 5-Gonane. 10  According to the number of carbons added to the steroidal backbone compounds are named, Estrane (C-18), Androstane (C-19), Pregnane (C-21), Cholane (C-24) and Cholestane (C-27). 11  If any double bond is present in the steroid skeleton, the "ane" ending of the stem name is replaced by "ene" if one double bond is present, "diene" if two double bonds are present and "triene" if three double bonds are present, and so on. 12  If the double bond is between sequentially (successively) numbered carbons, the position(s) of the double bond is indicated by the number of the lowest C-atom involved in the double bond. If the double bond is not between tow sequentially (successively) numbered carbons, both carbons are indicated in the name and first number is followed by the number of the second carbon atom, placed in parentheses 13  Substitution on the carbon skeleton should be designated - or - and the priority of the given suffix (stem name) is based on the oxidation state of the substituents. All the human steroidal hormones are biosynthesized from the Cholestane based sterol (steroidal alcohol) Cholesterol (Cholest-5-en-3-ol). (can you draw it?) 14 Cholesterol (Cholest-5-en-3-ol). 15  Steroidal Hormones, Receptors and Mechanism of Action Within the human body, there are two main types of steroidal hormones, Sex hormones and Adrenocorticoids. Three main categories of sex hormones are secreted in the human body, Estrogens (associated with the physiology of the female), Progesterone (the progestational hormone, associated with the physiology of gestation), Androgens (mainly Testosterone, associated with the physiology of the male). 16  Estrogens, Progesterone and Testosterone are produced in both males and females, but the relative amounts and patterns of secretion differ markedly between the sexes. Females primarily secrete Estrogens and Progesterone, whereas males primarily produce Testosterone, which are the cause of the development of the complementary reproductive systems and characteristic physical differences of women and men. 17 18  The overall mechanism of steroidal hormone action is the regulation of tissue-specific gene expression and protein biosynthesis in target cells. The individual hormones exhibit remarkable tissue selectivity, even though their structural differences are relatively minor. The basis for this selectivity is the presence of selective steroid hormone receptors in individual tissues. 19 Mechanism of action steroid hormones pass through the plasma membrane and act in a two step process. 1. Steroid hormones bind, once inside the cell, to the nuclear membrane receptors, producing an activated hormone-receptor complex. 2.The activated hormone- receptor complex binds to DNA and activates specific genes, increasing production of proteins. 20  Adrenal Steroids (Adrenocorticosteroids, Adrenocorticoids, Corticosteroids or Corticoids) The adrenal gland secrets two types of hormones, the adrenal medulla secrets catecholamines (mainly epinephrine) and the adrenal cortex secrets adrenal steroids (adrenocorticosteroids or simply corticosteroids). The adrenal cortex produces two main types of steroidal hormones, mineralocorticoid (MC) and glucocorticoid (GC). 21 Mineralocorticoid Glucocorticoid (Aldosterone) (Cortisol,Hydrocortisone) maintains salt and regulates carbohydrates, lipids water balance of the and protein metabolism body (concerns mainly with glucose its secretion is mobilization and metabolism), controlled by the it also inhibits inflammatory rennin-angiotensin reactions and suppresses system. immunity. 22  Corticosteroids Phospholipase A2 NSAIDs Cyclooxygenase Lipoxygenase Leukotrienes 23  The secretion of Cortisol is primarily controlled centrally by hypothalamus (through corticotropin) and the pituitary gland through the Adrenocorticotropic Hormone (ACTH). Cortisol and other glucocorticoids act as feedback inhibitors of both ACTH and corticotropin. This is why exogenously administered glucocorticoids can inhibit endogenous Cortisol production, leading to adrenal insufficiency when the exogenous glucocorticoid is withdrawn. 24  Therapeutic Uses of Synthetic Adrenal Steroids Adrenal insufficiency (Addison’s disease). Rheumatoid disease and allergic manifestations (e.g. severe asthma, rheumatoid arthritis, rheumatic fever). Suppression of inflammations regardless to their cause. Corticosteroids are neither specific nor curative treatment. 25 Adverse Effects of Adrenal Steroids Salt and water retention (hypertension and Cushing’s Syndrome) Redistribution of body fat (Buffalo hump, Moon face). Enhance lipolysis and increase Triglycerides. Inhibition of prostaglandins synthesis may aggravate peptic ulcers. Increase gluconeogenesis leading to glucose intolerance. 26  Structure Activity Relationships for Corticosteroids Essential structure features are: Insertion of α-CH3 groups oC=O at C3 at positions 6 and 16 oA double bond between. C4 &C5 (in 11β-OH analogs) will oOxygen a C11 (C=O or OH) increase glucocorticoid activity. oβ-ketol side chain at C17 16α or β-CH3 blocks The 9α-F group increases hydroxylation thus glucocorticoid activity by: enhancing potency o Preventing metabolic oxidation All trans (B/C and C/D) Insertion of 16α- of 11 β-OH to C=O backbone is necessary OH group o Increasing dissociation of for the activity. 11 β-OH so, increasing the decreases sodium formation of H-B to biological Insertion of a double retention by receptor bond between C1 and o Opposing the C2 increases effect of 9α-Fluoro glucocorticoidal activity. (Increasing sodium excretion.) 27 Insertion of bulky substituents on the β- Many functional groups such as side of the molecule abolishes glucogenic 17α-OH, 17α-CH3, 16α-CH3 and activity, while insertion on the α-side does 16 β-CH3 abolish or reverse the not. sodium retaining activity in 11- deoxycorticosterone. Association of these steroids with their receptors involves the β-surfaces of rings C and D, and the β-ketol side chain. Conversion of 17-hydroxyl to either a 17-ester or an ether as with 16, 17 acetonide greatly enhances the anti-inflammatory potency and glucocorticoid receptor affinity. 28  a. Systemic Glucocorticoids Cortisone is the 11-keto analog of Cortisol, in vivo it is reduced to the endogenous more active hormone, it is orally active and is the drug of choice for replacement therapy in patients with adrenocorticol insufficiency. Cortisone Cortisol (Hydrocortisone) 17a,21-Dihydroxy pregn-4-en-3,11,20-trione 11b,17a,21-Trihydroxy pregn-4-en-3,20-dione 29  Metabolism: Hydrocortisone hydrocortisone is rapidly but reversibly metabolized to inactive cortisone by 11β–hydroxysteroid dehydrogenase type-1(1β-HSD1). Present in the liver [“liver” isozyme] It limits the oral use of hydrocortisone and regulates hepatic gluconeogenesis in the liver and fat production in adipose tissues. 11β-HSD1 11β-HSD2 Cortisol (Hydrocortisone) Cortisone 11b,17a,21-Trihydroxy pregn-4-en-3,20-dione 17a,21-Dihydroxy pregn-4-en-3,11,20-trione Hydrocortisone is inactivated to cortisone by 11β hydroxysteroid dehydrogenase type-2 (11β-HSD2). Present in the Kidney [“KIdney” isozyme] This action helps in protecting the mineralocorticoid receptor (which is a non-selective receptor) from being occupied by the glucocorticoids. Deficiency of this enzyme results in 30 “Apparent Mineralocorticoid Excess” (AME syndrome).  Metabolism: Hydrocortisone 11β–hydroxysteroid dehydrogenase is present in the form of 2 isoforms 11β-HSD1 11β-HSD2 Present in the liver Present in the Kidney Hydrocortisone is inactivated to hydrocortisone is rapidly but cortisone by 11β hydroxysteroid reversibly metabolized to inactive dehydrogenase type-2 (11β-HSD2). cortisone by 11β–hydroxysteroid Present in the Kidney dehydrogenase type-1 [“KIdney” isozyme] ((11β-HSD1). Present in the liver This action helps in protecting the [“liver” isozyme] mineralocorticoid receptor (which is It limits the oral use of a non-selective receptor) from being hydrocortisone and regulates occupied by the glucocorticoids. hepatic gluconeogenesis in the Deficiency of this enzyme results in liver and fat production in adipose “Apparent Mineralocorticoid Excess” tissues. (AME syndrome). 11β-HSD1 11β-HSD2 31 Cortisol (Hydrocortisone) Cortisone  Synthetic Corticosteroids Most glucocorticoids have some mineralocorticoid effect, usually considered as undesirable activity. Molecular modifications are done to separate the two activities i.e.: increase anti-inflammatory activity and decrease of salt and water retention effect. 32  Prednisone and Prednisolone are dehydro derivative of Cortisone and Hydrocortisone (1-corticoids), they have about 4 times the anti-inflammatory activity of their parent compounds. Cortisol(Hydrocortisone) 11b,17a,21-Trihydroxy pregn - 4-en-3,20-dione 33  The increased potency of 1-corticoids is due to the change in geometry of ring-A which increases receptor affinity. 34  Methylprednisolone has similar glucocorticoid activity as Prednisolone, but it has less sodium and potassium retention. The 6-methyl substitution hinders the metabolic oxidation at this position increases the lipid solubility enhances oral bioavailability. Prednisolone Methylprednisolone 35  9α-Fluoro substitution markedly increases the anti-inflammatory potency but also enhances the mineralocorticoid activity of hydrocortisone. Addition of a position-1 double bond (1-corticoid structure) to the 9α-Fluorocorticoid balances the activity, 16-methyl group increases the lipid solubility and enhances the bio availability, e.g. Betamethasone. Prednisolone Betamethasone 36  Dexamethasone is the 16- analog has longer duration as the 16-methyl group stabilizes the 17-ketol side chain to metabolism and improves bioavailability. Dexamethasone 37  Triamcinolone is another example of 1-Fluorocorticoid with 16-hydroxyl group possessing enhanced glucocorticoid activity. It is active orally its cyclic ketal (or acetal) derivative with acetone is a glucocorticoid that is used mainly topically. 38  The choice of systemic glucocorticoid is made according to properties required: Hydrocortisone and Cortisone have glucocorticoid effects but relatively high mineralocorticoid activity. They are therefore unsuitable for long term use, but useful intravenously in emergency situations. Hydrocortisone can be used topically with less risk of side effects. Prednisolone has high glucocorticoid activity with less mineralocorticoid effect and is used for longer term treatment. 39  Betamethasone and Dexamethasone have even higher glucocorticoid activity and insignificant mineralocorticoid effect. They can thus be used when high dosages are required without effects such as fluid retention (e.g. cerebral edema from malignancy). They cross the placenta readily and should be avoided in pregnancy. Their long duration of action makes them useful in conditions like congenital adrenal hyperplasia when suppression of corticotrophin must be maintained. 40 The following table summarize the glucocorticoid and mineralocorticoid activity of some corticosteroids Drug Glucocorticoid Mineralocorticoid activity activity Cortisol 1.0 1.0 Cortisone 0.8 0.8 Prednisone 4