Steroids

Lucid explanation of basics of steroids medicinal chemistry point of view.

1. Steroids medicinal chemistry PREPARED AND PRESENTED BY: Mr. Dharmendrasinh A Baria , Assistant Professor Pharmaceutical Chemistry Department Smt. S. M. Shah Pharmacy College Aamsaran , Mahemdabad Gujarat DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 1

2. Steroids comprise a group of cyclical organic compounds whose basis is a characteristic arrangement of seventeen carbon atoms in a four ring structure linked together from three 6-carbon rings followed by a 5-carbon ring and an eight-carbon side chain on carbon-17 (illustration on right). DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 2 Cyclopentanoperhydrophenanthrene

3. CHOLESTEROL “Cholesterol is the most highly decorated small molecule in biology. Thirteen Nobel Prizes have been awarded to scientists who devoted major parts of their careers to cholesterol. Ever since it was isolated from gallstones in 1784, cholesterol has exerted an almost hypnotic fascination for scientists from the most diverse areas of science and medicine…. Cholesterol is a Janus-faced molecule. The very property that makes it useful in cell membranes, namely its absolute insolubility in water, also makes it lethal.” DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 3

4. Cholesterol is the most abundant steroid in animals Plants have very small amounts (but have related compounds). It’s a major component of cell membranes, and affects the fluidity of the membrane due to its bulky structure. Is a precursor for biosynthesis of many other steroids. Cholesterol is called a sterol because it contains an alcohol group. We can obtain cholesterol from our diet (animal products), but our liver can also synthesize all the cholesterol that we need. The liver synthesizes more cholesterol when dietary intake is low. Excessive blood cholesterol is associated with atherosclerosis and formation of gallstones. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 4

5. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 5 CHOLESTEROL IS THE BIOSYNTHETIC SOURCE OF ALL STEROIDS

6. STEROID NOMENCLATURE, STEREOCHEMISTRY , AND NUMBERING Nearly all steroids are named as derivatives of cholestane (C27), androstane (C19), pregnane (C21), or estrange (C18). The standard system of numbering is illustrated with 5 α - cholestane ( the H8 and H9 protons have been omitted here for clarity ). DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 6

7. The absolute stereochemistry of the molecule and any substituents is shown with solid ( β ) and dashed ( α ) bonds . Most carbons have one β bond and one α bond , with the bond lying closer to the “top” or C18 and C19 methyl side of the molecule. Both α - and β -substituents may be axial or equatorial . This system of designating stereochemistry can best be illustrated by the use of 5 α - androstane . DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 7

8. The stereochemistry of the H at C5 is always indicated in the name. The stereochemistry of the other H atoms is not indicated , unless it differs from 5 α - cholestane . Changing the stereochemistry of any of the ring juncture or backbone carbons (shown with a heavy line on 5 α - cholestane ) greatly changes the shape of the steroid, as seen in the examples of 5 α , 8 α - androstane and 5 β - androstane . The terms cis and trans are occasionally used in steroid nomenclature to indicate the backbone stereochemistry among rings. For example, 5 α - steroids are A/B trans, and 5 β - steroids are A/B cis . The terms syn and anti are used analogously to trans and cis for indicating stereochemistry in bonds connecting rings (e.g., the C9:C10 bond that connects rings A and C). DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 8

9. The position of double bonds can be designated in any of the various ways shown in Figure. Double bonds from C8 may go toward C9 or C14, and those from C20 may go toward C21 or C22. In such cases, both carbons are indicated in the name if the double bond is not between sequentially numbered carbons (e.g., 5 α -androst-8(14 )- ene or 5 α - Δ 8 ( 14) - androstene ). DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 9

10. FROM CHOLESTEROL TO STEROID HORMONES DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 10

11. CLASSIFICATION OF STEROIDS Sterol Also known as steroid alcohols. Occur naturally in plants, animals, and fungi, with the most familiar type of animal sterol being cholesterol. TYPES Phytosterols – plant sterol ( Campesterol , Sitosterol , and Stigmasterol ). Blocks cholesterol absorption sites in the human intestine, thus helping to reduce cholesterol in humans. Zoosterol – animal sterol (Cholesterol). Ergosterol – sterol present in the cell membrane of fungi. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 11

12. Camptosterol Sitosterol Stigmasterol Cholesterol Ergosterol DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 12

13. Bile acids Are steroid acids found predominantly in the bile of mammals and other vertebrates. Are conjugated with taurine or glycine in the liver, forming bile salts. Primary bile acids are those synthesized by the liver. Secondary bile acids result from bacterial actions in the colon. functions: To remove unwanted cholesterol from the body To aid in lipid digestion in the intestine DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 13 Taurocholic acid Glycocholic acid

14. Cardiac Glycosides Are glycosides of mostly C23-steroidal compounds. Are called cardiac glycosides because they modify heart action. Medicinal importance They are cardiotonics used to treat Congestive heart failure (CHF). They increase force of contraction of cardiac muscles without increase oxygen consumption. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 14 Digitoxin Digoxin

15. Steroid hormones A steroid that acts as a hormone Can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens , estrogens , and progestogens. Steroid hormones help control Metabolism , inflammation, immune functions, salt and water balance, development of sexual characteristics, and the ability to withstand illness and injury. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 15

16. BIOSYNTHESIS OF STEROID HORMONES DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 16

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18. Cortisol (Hydrocortisone) Glucocorticoids Glucocorticoids originate in the adrenal cortex and affect mainly metabolism in diverse ways; decrease inflammation and increase resistance to stress. Cortisol (C-21): dominant glucocorticoid in humans, synthesized from p rogesterone in the zona fasciculata of the adrenal cortex, involved in stress adaptation, elevates blood pressure and Na+ uptake, numerous effects on the immune system. CLASSES OF STEROID HORMONES DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 18

19. Mineralocorticoids Mineralocorticoids originate in adrenal cortex and maintain salt and water balance. Aldosterone (C-21) : the principal mineralocorticoid, produced from progesterone in the zona glomerulosa of adrenal cortex, raises blood pressure and fluid volume, increases Na+ uptake. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 19 Aldosterone

20. ESTROGENS Estrogens originate in the adrenal cortex and gonads and primarily affect maturation and function of secondary sex organs (female sexual determination ). The natural estrogenic hormones are estradiol , estrone , and estriol , produced in the gonads, adrenals, and placenta. Estradiol (C-18): an estrogen , principal female sex hormone, produced in the ovary, responsible for secondary female sex characteristics. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 20 Estrone Estratriol Estradiol

21. Testosterone ANDROGENS Androgens originate in the adrenal cortex and gonads and primarily affect maturation and function of secondary sex organs (male sexual determination). Testosterone (C-19): an androgen, male sex hormone synthesized in the testes, responsible for secondary male sex characteristics, produced from progesterone; most potent androgen in blood. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 21

22. PROGESTINS Progestins originate from both ovaries and placenta, and mediate menstrual cycle and maintain pregnancy. Progesterone (C-21): a progestogen, produced directly from pregnenolone and secreted from the corpus luteum, responsible for changes associated with luteal phase of the menstrual cycle, differentiation factor for mammary glands. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 22 Progesterone

23. ADRENAL CORTICOSTEROIDS Adrenal corticosteroids are hormones produced in the adrenal glands (located just above the kidneys). Cortisone (a glucocorticoid) raises the blood glucose level by causing tissues other than the brain to switch to metabolizing fats and proteins; it also suppresses the immune response and can be used as an anti-inflammatory anti-allergy medication. Aldosterone (a mineralcorticoid ) regulates ion balance by promoting re- absorbtion of Na + , Cl - and HCO 3 - by the kidneys. Prednisone is a synthetic corticoid used to treat various inflammatory conditions, such as asthma and rheumatoid arthritis. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 23

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25. CLASSIFICATION OF CORTICOSTEROIDS Mineralocorticoids with high salt retention DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 25 Aldosterone 11-Deoxycorticosterone Fludrocortisone Cortisone acetate Hydrocortisone  Prednisone Prednisolone 2. Glucocorticoids with moderate-to-low salt retention

26. Betamethasone Dexamethasone Methylprednisolone 3. Ophthalmic glucocorticoids Fluorometholone   Loteprednol etabonate Rimexolone DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 26

27. 4. CORTICOSTEROIDS USED FOR THE TREATMENT OF ASTHMA AND ALLERGY DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 27 Triamcinolone Beclometasone diproprionate Budesonide Fluticasone propionate   Mometazone furoate Flunisolide

28. ACTIONS OF CORTICOSTEROIDS Direct (Intended) Actions Anti-inflammatory Anti-allergy Anti-immunity Permissive Actions Lipolytic effects Effect on BP Effect on bronchial muscles DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 28

29. Glucocorticoids ( e.g ., prednisolone) used to suppress inflammation, allergy and immune responses. Anti-inflammatory therapy is used in many illnesses ( e.g ., Rheumatoid Arthritis, Ulcerative Colitis, Bronchial Asthma, eye and skin inflammations). Useful in, say, tissue transplantation and lymphopoiesis ( leukemias and lymphomas). Striking improvements can be obtained, but severe adverse, but highly predictable, effects ensue . DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 29

30. Hydrocortisone used orally for replacement therapy, i.v. for shock and asthma, topically for eczema (ointment) and enemas (ulcerative colitis). Triamcinolone used for severe asthma and for local joint inflammation. Betamethasone and Dexamethasone : Very potent, w/o salt-retaining properties; thus, very useful for high-dose therapies ( e.g ., cerebral edemas ). Beclometasone diproprionate , Budesonide : Pass membranes poorly; more active when applied topically (severe eczema for local anti-inflammatory effects) than orally; used in asthma, (aerosol). DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 30

31. MINERALOCORTICOIDS Aldosterone is a steroid hormone (mineralocorticoid family) produced by the outer section (zona glomerulosa) of the adrenal cortex in the adrenal gland. It plays a central role in the regulation of blood pressure , Increasing reabsorption of ions and water in the kidney , Aldosterone is pathogenic and contributes to the development and progression of cardiovascular and renal disease, Aldosterone has exactly the opposite function of the atrial natriuretic progression of cardiovascular and renal disease, Hormone secreted by the heart. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 31

32. Fludrocortisone has a very great sodium-retaining effect in relation to its anti-inflammatory action and only at high doses the nonelectrolyte effects need to be considered. It is used to replace aldosterone where the adrenal cortex is destroyed ( Addison's disease ). Fludrocortisone is also the drug of choice in most patients with autonomic neuropathy , in whom volume expansion is easier to achieve than a sustained increase in vasoconstrictor tone. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 32

33. SAR OF CORTICOSTEROIDS Modification in Ring A Contraction of ring A to norcortisol yields and inactive compound. Ring A can be modified isosterically to a heterocycle like 2-Oxacortisol acetate, which has 25% activity of the cortisol. The introduction of unsaturation (a double bond) at C-1 leads to enhanced anti-inflammatory activity (ex. Betamethasone). Whereas the addition of –OH group leads to the compound becoming inactive. The introduction of a 2 α -methyl group into cortisol leads to increase in activity, the C-2 bromo substituent is potent among the halogens. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 33 Hydrocortisone (cortisol) is the naturally occurring glucocorticoid with mineralocorticoid activity.

34. The C-3 carbonyl group can be fused with a heterocyclic moiety to yield a ‘soft drug’. C-3 spirofused thiazolidine derivative (1) was found to be active and this derivative considerably reduced the thinning of the skin, generally found in corticosteroids. but not essential for anti-inflammatory activity. Ex. 5 α - Pregnane - 3-one. The Δ 4 double bond is important. Ring A can be fused with a pyrazole ring. Compound (2) has 2000 times the potency of cortisol, but also lacks mineralocorticoid activity. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 34 (1) Cortisone 5 α -Pregnane-3-one. (2)

35. Modification in Ring B Substitution of 6 α position with hydrophobic groups like alkyl or halogens (methyl, chloro and fluoro leads to increase in activity. Polar substituents such as –OH or =O at 6 α position decreases the activity. 7 α and 7 β substituents decrease the anti-inflammatory activity. Thus 7 α and 7 β methyl cortisol derivatives are less potent than cortisol. Introduction of –OH group at both 6 α and 7 α position leads to decrease in activity. 6 α and 7 α difluoromethylene and 6 β and 7 β derivatives show enhanced activity. Introduction of 8(9) double in prednisolone affords compound with lower anti-inflammatory activity. Removal of the C-19 angular – CH 3 group reduces anti-inflammatory activity. The H at C-10 should be in β -configuration for the optimal activity. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 35

36. Anti-inflammatory potency of corticosteroids drastically influenced by the substituents at C-9 position. The groups added were –F, -Cl, -Br, -I, -OH and – CH 3 . The activity of the compounds increases with increasing hydrophobic bonding of the C-9 α substituents. The function of the electron withdrawing group at C-9 was to increase the activity of the neighbouring 11 β -hydroxyl group which in turn leads to increase in corticoid activity. Modification of Ring C The C-11 oxygen group is not essential for anti-inflammatory activity. It can be replaced by groups like –Cl, which can be converted to the hydroxyl group in vivo . Ester substituents at C-12 have showed anti-inflammatory activity and the potency is in the following order: propinyl >butyl > isovaleryl . Modification in ring D Methyl group at C-15 with α configuration enhances anti-inflammatory activity . Placement of 16α- hydroxy and 17α- hydroxy groups yields potent compounds. These two groups DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 36

37. Modification in the side chain at C-17 Acetonide derivatives across the 17, 20-diol arrangement resulted in more potent analogues compared to free diols . Hydroxyethanone side chain attached at C-17 in the classical corticosteroid is not essential for activity. Tipredane , a 17-thioketal is a potent topical anti-inflammatory drug. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 37 Tipredane may also form acetonide derivatives, which are more potent than the corresponding 16, 17-dihydroxy derivatives. At C-16 introduction of chloro , methyl groups increase activity. The 17 α -OH group is not essential for activity. Ketals and esters yield compounds with improved potency. Introduction of –Cl, -Br and –F at C- 17 α position lowers the activity.

38. Replacement of the –OH group at C-21 by –Cl, or –F enhances activity. Retaining of anti-inflammatory activity of corticosteroids observed upon ketalization of the C-20 carbonyl group with ethylene glycol. Replacement of the C-21 carbon by sulphur (fluticasone) afforded 21-thioesters, also useful clinically. The C-21 –OH group can be esterified to afford lipophilic compounds that are meant for respiratory use. Introduction of activating groups at C-21, conversion of –CH 2 OH group to a – CH 3 group ( medrysone ) yields clinically useful ophthalmic anti-inflammatory compound with relatively little effect on intraocular pressure. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 38 Fluticasone Medrysone

39. ANDROGENS & ANABOLIC STEROIDS The term androgens includes a number of natural and synthetic compounds that exhibit the masculinizing and anabolic action of testosterone . The main physiological, endogenic, and androgenic hormones. Androgen, commonly referred to as male sex hormones or anabolic steroids, in particular, testosterone, are produced by male sex glands in the male body. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 39

40. Common Anabolic Androgenic Steroids DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 40

41. Testosterone is the natural androgen secreted by the interstitial cells of the testis; it is necessary for normal spermatogenesis, for the development of the male secondary sex characteristics, and for the growth, at puberty, of the sexual apparatus. It is converted by hydroxylation to the active dihydrotestosterone . Protein anabolism especially in skeletal muscles is increased by androgens. Growth of bone is promoted , but the rate of closure of the epiphyses is also hastened, causing short stature in cases of precocious puberty or of androgen overdose in the course of treating hypo gonadal children . DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 41

42. PATHWAY OF SYNTHESIS OF TESTOSTERONE IN THE LEYDIG CELLS OF THE TESTES DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 42

43. METABOLISM OF TESTOSTERONE TO ITS MAJOR ACTIVE AND INACTIVE METABOLITES DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 43

44. SAR OF ANDROGENS For a substance to have activity, it must contain the androstane skeleton. Oxygen at C-3 and C-17 are not essential for the androgenic activity. The basic nucleus having 5 β - androstane which having androgenic activity, whereas 5 α - androstane having no activity. There should not be chain constriction or extension because it leads to finished the activity. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 44

45. Introduction of 3-hydroxy group and 3-keto group enhance the activity. Hydroxy group at C-17 position has no androgenic or anabolic activity. Halogen substitution produces compounds with decreased activity except when placed at C-4 or C-9 position. For example, 9-fluoro derivatives produces an anabolic effect 20 times that of 17 α -methyl testosterone DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 45 Fluoxymesterone 17 α -methyl testosterone

46. Halogen introduction will decrease the activity except the C-4 and C-9 . Introduction of double bond at C-1 position increases the anabolic activity for example – methandrostenolone is more active than methyltestosterone . Replacement of carbon atom at C-2 position by oxygen (e.g. O xandrolone ) gives the oral anabolic activity . DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 46 Methandrostenolone Methyltestosterone Oxandrolone

47. Removal of – CH 3 group in testosterone gives 19-nor testosterone with more anabolic activity and less androgenic activity when compared with testosterone. The introduction of heterocyclic system into the steroid nucleus in ring A improve the anabolic activity. For example, stanozolol are found to possess more anabolic activity, possessing pyrazole . DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 47 19-nor testosterone Stanozolol

48. ESTROGENS Estrogen are a group of steroid compounds that function as the primary female sex hormones. Three naturally occuring estrogen are estradiol,estriol and estrone , In the body these are all produced from androgens through enzyme action . SOURCE:- Estrogen are produced by developing follicles in the ovaries, the corpus luteum and the placenta, some estrogens are also produced in smaller amounts by other tissues such as liver, adrenal glands and the breasts . These secondary source of estrogen are especially important in post menopausal women. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 48

49. THE BIOSYNTHETIC PATHWAY FOR THE ESTROGENS DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 49

50. CLASSIFICATION OF ESTROGENS STEROIDAL ESTROGENS DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 50 Estradiol Estrone Estriol Ethinyl estradiol  Mestranol

51. 2. NON STEROIDAL OR SYNTHETIC ESTROGENS DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 51 Diethyl stilbestrol Dienestrol Hexestrol 3. ESTROGENS OF PLANT ORIGIN Coumestrol Genistein

52. ESTRADIOL Estradiol is a human sex hormone and steroid, and the primary female sex hormone . It is important in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is essential for the development and maintenance of female reproductive tissues but it also has important effects in many other tissues including bone. While estrogen levels in men are lower compared to women, estrogens have essential functions in men as well . Uses: It helps to regulate and subsequent maintence of female sex organs, certain function of the uterus and all the secondary sex features and the mammary glands . DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 52

53. SAR OF ESTROGEN Modification of ring A Ring A is aromatic in nature in all oestrogens, which is essential for oestrogenic activity. -OH group at C-3 is also essential for oestrogenic activity. Removal of this –OH group leads to loss of activity. Substitution at C-1 reduces the activity. Smaller groups can be substituted at positions C-2 and C-3. Ex. 2-hydroxyl ethinyl estradiol . DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 53 Presence of steroid nucleus ( cyclopentanoperhydrophenanthrene ring) is essential for pharmacological activity of oestrogen. Estrone Estriol

54. Modification of Ring B Presence of unsaturation at positions C-6 and C-7 increase the potency of drug. Similarly additional double bond between C-8 and C-9 positions further increase the activity. Ex. e quilin , equilenin . 7 α -substituents show increased activity. Modification of Ring C Substitution of –OH groups at C-6, C-7 and C-11 position reduces the activity. Substitution at C-11 β -position with alkyl group or alkoxy groups which has 17-ethinyl group greatly increase affinity for the estrogenic receptor compared to estradiol . Ex. 11 β - methoxy or 11 β -ethyl estradiol . – CH 2 Cl group at C-11 with β -configuration shows more potent activity. Larger substituents, ex. N,N- dialkyl undecylamides , shows antagonistic activity. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 54 Equilin Equilenin

55. Modification of Ring D 17 β -OH is essential for estrogenic activity. Epimerization of 17 β -OH to a α -configuration results in the formation of less active analogues. 17 α - Ethinyl or 17 α -vinyl groups provide greatest activity due to increase in polarity. Ex. Ethinyl estradiol . Reversal of configuration of C-2 or replacement of H for ethynyl in D ring leads to loss of estrogenic activity or increase in androgenic activity. The distance between C-3 and C-17 –OH groups should be 11-12 Aᵒ, presence of this hydrophobic scaffolding helps to optimize estrogenic activity. Ex. All estrogens and diethylstilbestrol . DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 55 17 α - Ethinyl estradiol Diethyl stilbestrol

56. PROGESTINS They also called luteum hormones, mostly secreted by the corpus luteum portion of the ovary and the metabolised to various inactive products, e.g . pregnanediol . The metabolites are essentially excreted through urine . The natural progestational hormone is progesterone , which is secreted by the corpus luteum in the second part of the menstrual cycle . Small amounts are also secreted by the testis in the male and the adrenal cortex in both sex and large amounts are secreted by the placenta . DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 56

57. USES Prevent habitual abortion. For treatment of functional uterine bleeding resulting due to the lack of oestrogens and progesterone For treatment of dysmenorrhoea or painful menstruation Pregnancy diagnosis, Oral contraceptives, For treatment of an advanced carcinoma of breasts. To treat premature discomfort in the breasts Progesterone can be used to treat catamenial epilepsy. Progesterone also has a role in skin elasticity and bone strength, in respiration, in nerve tissue and in female sexuality, and the presence of progesterone receptors in certain muscle and fat tissue. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 57

58. CLASSIFICATION DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 58 1. Derivatives of progesterone  P rogesterone  17-Hydroxyprogesterone caproate Megestrol acetate Medroxyprogesterone acetate

59. 2. Synthetic progesterone DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 59 Ethisterone   Norethisterone Dimethisterone Noretynodrel Desogestrel   L evonorgestrel  

60. SAR OF PROGESTERONE Presence of steroid nucleus ( cyclopentanoperhydrophenanthrene ring) is compulsory for pharmacological activity of progestins . Ketone group at C-3 is not essential for the activity of progesterone, because removal of it retains the progesterone. Ex. Desogestrel . Presence of ethyl or ethinyl or diethyl group at C-17 in α configuration increase bioavailability through oral route, but decreases by subcutaneous route. The l-enantiomer of the compound resulting from substitution of ethyl group at C-ring junctures found to be active. Derivatives of the progestins like 3-oxime-17-ester decreases androgenic side effect, while retaining progestin activity. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 60 Progesterone Desogestrel Ethisterone

61. Introduction of halogen or –CH 3 at C-6 or C-7 atoms in α configuration increases hormonal activity of progestins . Ex. Medroxyprogesterone acetate. Presence of methyl at C-19 is not essential for activity because its removal leads o formation of compound with increased activity. Addition of Cl or F at C-21 prevents metabolic hydroxylation, which also enhances oral effectiveness. Unsaturation at ring A and B enhances activity of 19-norethindrone. Ex. Trimegestone . Addition of methyl at 18 th position increases the activity. In ring D at C-17, acetylation of 17 α -hydroxyl group increases the duration of action. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 61 Medroxyprogesterone acetate   Norethisterone

62. Mechanism of Steroid Hormone Action Steroid hormones are soluble in the plasma membrane and readily enter the cytosol . Steroids bind to intracellular receptor either in the cytosol or in the nucleus . The hormone-receptor complex acts as a transcription factor which turns on / turns off the genes . DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 62

63. REFERENCES J. N. Delgado and W. A. Remers , Wilson & Gisvold's : Textbook of Organic Medicinal and Pharmaceutical Chemistry, Tenth edition, Lippincott Raven Publishers, Philadelphia, New York 1998. S. N. Pandeya : A Textbook of Medicinal Chemistry, Vol-2, S.G. Publishers, Varanasi, 2003. Ashutosh Kar , Medicinal Chemistry, 3rd edition, Wiley Eastern, Ltd, New Delhi,2005 . Dr V. Alagarsamy , Textbook of Medicinal Chemistry, Vol. II, Elsevier India, 2013. K. D. Tripathi ., Essentials of medical pharmacology, Jaypee Brotter Medical Publisher (p) LTD, 5 th edition. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 63

64. DHARMENDRA BARIA, Smt. S.M. Shah Pharmacy College 64 THANK YOU