Chapter 11 Hormones （ 2 ）

1. Chapter 11 Hormones（2） Pei Yu College of Pharmacy Jinan University

2. 3.Steroid Hormones 3.1 Steroid Estrogen (雌激素)3.2 Non-Steroidal Estrogen & Selective Estrogen Receptor Modulator 3.3 Male Hormones & Protein Anabolic Hormones (蛋白同化激素) 3.4 Progestogen Hormone (孕激素) 3.5 Steroid Contraceptive agents (避孕药) 3.6 Anti-progestogen（孕激素拮抗剂） 3.7 Adrenocorticoids (肾上腺皮质激素)

3. 3.3 Male Hormones and Protein Anabolic Hormones(蛋白同化激素) • Male hormones have male activity and protein assimilation (同化) activity. • Some structure modified compounds which are called protein anabolic hormones(蛋白同化激素)have very weak male activity but strong protein assimilation activity. • Anabolichormones are drugs derived from the male sex hormone to promote growth or to help the body repair tissues weakened by severe illness or aging, and it subject to abuse to promote muscle mass in athletes. • The purpose to modify male hormones is to acquire new protein anabolic hormones .

5. Anabolic Hormones • Promote protein anabolism(合成代谢)and reduce its catabolism(分解代谢). • Enhance the procedures of protein synthesis from amino acid. • Clinical uses of anabolic hormones are treating sickness asthenia(虚弱), cacotrophia(营养不良)of new-born and aged people, consume diseases, osteoporosis and gastric and duodenal ulcer (胃十二指肠溃疡)etc .

6. Side-effect of Anabolic Hormones • Male activity is the main side-effect of anabolic hormones. • Minor change of structure of Testosterone(睾酮)can cause male activitydecrease and anabolic activityincrease. For example: • De-methyl on C-19; • Substitution on ring A • Fused rings of ring A • No anabolic hormones without male activity . 19 A

7. Common Male Hormones and Anabolic Hormones

8. Testosterone Propionate(丙酸睾酮) 17 • Chemical name： 17-Hydroxyandrost-4-en-3-one propionate 3 4

9. Structure of Testosterone Propionate • Testosterone is a natural male hormones. Separated from male cow testis(睾丸) in 1935. • It is △4-3-ketone and 17β-hydroxyl compound,and here it is propionate. • UV absorption.

10. Absorption and Pharmacokinetics • By oral Testosteronecannot be absorbed in gastrointestinal tract, but Testosterone Propionate oil solution has prolonged effect in vivo because it can be hydrolyzed and release Testosterone slowly. • Testosterone propionate — Pro-drug.

11. Biotransformation • The ratio of activity: Dihydrotestosterone ：Testosterone ： △4-Androstenedione(雄烯二酮) = 150：100 ：10 5α-Reductase Dihydrotestosterone Testosterone 17 β- dehydrogenase △4 –Androstenedione

12. Analogues of Testosterone The advantage of 17α-methyl analogue: • rapid oral absorption, • finebioavailability, • can not be decomposed in liver. valerate undecylenate Prolonged effect.

13. Synthesis of Testosterone Oppenauer Dehydrotestosterone

14. 3.4 Progestogen Hormone(孕激素) • Progesterone(黄体酮) and 17α- hydroxy-progesterone are natural progestogens (孕激素). • Use together with estrogen hormones to keep female reproductive cycle and physiological character. • The preparations of progestogen hormones combined with estrogen hormones are used as oral contraception agents(口服药避孕药). • Offset side-effects in estrogen replacement therapy.

15. Progesterone（黄体酮） • Chemical name : Pregn-4-ene-3,20-dione

16. Structure features C-21-Steroids with △4-3-ketone Progesterone (黄体酮) Testosterone (睾酮)

17. 17α-Substitute Progesterone（ Oral ） • The first effective oral Progesterone drug is not derived from Progesterone, but a Testostrone analogue — Ethisterone(炔孕酮). • When ethynyl(乙炔基) group at C-17 of Testostrone is added, its male activity lessened and progestogen activity strengthened, it can be orally used.

18. Then 17α-Hydroxyprogesterone was found during biosynthesis studies of cortical hormone. The activity of its acetate is only 1% of Norethisterone (炔诺酮). • 17α-Hydroxyprogesterone Caproate(己酸酯) has a prolonged activity, which oil injection can be used once a month . No methyl R= -CH3 hydroxyprogesterone acetate R= -C5H11 hydroxyprogesterone caproate

19. Medroxyprogesterone Acetate(醋酸甲羟孕酮) • Chemical name: (6  )-17-Hydroxy-6-methylpregn-4-ene-3, 20-dione acetate

20. Metabolism of Progesterone Activity are lessened!

21. Oral Potent Progestin(黄体激素) • The C-6 analogues 6 6 6

22. 3.5 Steroid Contraceptive agents(避孕药) Levonorgestrel(左炔诺孕酮) • Chemical name: D-(-) 17-Ethynyl-17- hydroxy-18-methyl-estro-4-en-3-one

23. Chemical structure of Levonorgestrel is similar as Norethisterone(炔诺酮) except C-13 ethyl substitution. • Levonorgestrel(左炔诺孕酮)is the active configuration of the drug, while Dextronorgestrel(右炔诺孕酮) has no effect . No methyl D L

24. Synthesis of Levonorgestrel

25. Mifepristone（米非司酮） 3.6 Anti-progestogen（孕激素拮抗剂） • Chemical name: 11-[4-(Dimethylamino)-phenyl]-17-hydroxy-17-(1-propynyl)estra-4, 9-dien-3-one;

26. Hormone, its excitomotor and antagonist(激素、激动剂和拮抗剂) synthesized excitomotor Hormones Hormone antagonist pregnancy (hormone antagonist) estrogen (hormone antagonist)

27. Structure feature • Compare with Norethisterone(炔诺酮): C-9 ene 11 -[4-(dimethylamino)-phenyl] 17 propyne

28. Use of Mifepristone Mifepristone is used as an abortifacient(堕胎药)in the first two months of pregnancy, and in smaller doses as an emergency contraceptive(避孕药). • Medical termination of intrauterine pregnancies(子宫内妊娠)of up to 49-65 days gestation(妊娠). • Softening and dilatation of the cervix(宫颈扩张术) prior to mechanical cervical dilatation for pregnancy termination. • Labor induction in fetal death in utero(宫内死胎).

29. SAR of Mifepristone acetyl phenyl group can increase activity, while short fatty series will turn inhibitor to excitant. Any substitute will decrease the activity. If substitute moved to o- or m- position, it will influence on double bond forming to lower drug activity Increase oral activity . α- methyl, it will turn inhibitor to excitant. Any substitute has no the activity. methyl, methanol, or ester can’t change anti-corticosteroids activity .

30. Metabolism of Mifepristone N-demethyl N-dedimethyl Propynyl hydroxy

31. Synthesis of Mifepristone From Norethisterone, 8 steps

32. 3.7 Adrenocorticoids(肾上腺皮质激素) Classification of adrenocorticoids • 1．Mineralcorticoids（盐皮质激素）： • Oxygen atomsdo not exist at C-11 and C-17 at the same time. • Aldosterone(醛甾酮) , Deoxycorticosterone(去氧皮质酮) • 2．Glucocorticoids（糖皮质激素）： • Oxygen atoms do exist at C-11 and C-17 at the same time. • Hydrocortisone(氢化可的松), Cortisone(可的松)

33. Main Natural Adrenocorticoids Glucocorticoids 17 11 Mineralcorticoids

34. Structural of Adrenocorticoids(肾上腺皮质激素) • Pregnane backbone with △4-3, 20-di-one; 11,17, 21- hydroxyls. 17 11

35. Mineralocorticoids(盐皮质激素) • Aldosterone (醛甾酮)and deoxycorticosterone(去氧皮质酮). • Mineralocorticoids can regulate water and salt metabolism and keep the electrolyte balance in vivo, but it isn’t used in clinic widely. • Its metabolism antagonists is used as hydragogues(水泻剂). Aldosterone (醛甾酮)

36. Glucocorticoids(糖皮质激素) • Most of corticoids are Glucocorticoids. • Glucocorticoids are important drugs. • They have direct relationship with metabolism of sugar, fat, protein and body growth. • Glucocorticoids still keep influence on metabolism of water and salt more or less. Hydrocortisone (氢化可的松)

37. Hydrocortisone(氢化可的松) • Chemical name: 11, 17, 21-Trihydroxypregn-4-ene-3, 20-dione

38. Biosynthesis • Endogenous（内源的）Hydrocortisone is biosynthesized from cholesterol（胆固醇）via 17α-hydroxyl progesterone（ 17α-羟基黄体酮）by enzyme catalysis . 17α-Hydroxyl-Progesterone

39. Metabolism 20 △4, 3-酮被还原 C-20侧链断裂 Δ4, 3-ketone are reduced C-20 side-chain is cut down

40. How to modify the Glucocorticoids? Modification at C-21. Modification at C-1.

41. Modification at C-21 • Only C-21 hydroxyl can be esterified, other hydroxyl can’t be esterified easily because of steric hindrance . • C-11 Hydroxyl group is blocked by C-10 and C-18 methyl group. • C-17 hydroxyl group is blocked by side chain. Steric hindrance Esterify easily Esterify hardly

42. Hydrocortisone C-21 esterified analogues Drug Name Substituent group

43. Modification at C1 • Hydroprednisone acetate(醋酸泼尼松龙) can be prepared by dehydrogenation at C1-C2 to introduce double bond in the ring A from Hydrocortisone acetate. • Its anti-inflammation activity is 4 times of the leading compound while its sodium retention (钠潴留) activity is not changed.

44. Dexamethasone Acetate(醋酸地塞米松) • Chemical name: 9--Fluoro-11, 17, 21-trihydroxypregna-16-methylpregna-1, 4-diene-3,20- dione-21-acetate.

45. Use of Dexamethasone • Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid hormones. • It acts as an anti-inflammatory and immunosuppressant (免疫抑制剂). • Its potency is about 20-30 times that of hydrocortisone (氢化可的松) and 4-5 times of prednisone(强的松). • Shock: 4 to 8 mg intravenously initially, repeat if necessary to a total dose of 24 mg. • Autoimmune diseases and inflammations: longterm therapy with 0.5 to 1.5 mg oral per day. Avoid more than 1.5 mg daily because of serious side effects.

46. Structure feature • All substituents on the pregnane(孕甾烷) backbone. Most important!

47. Reaction with sodium sulfite • Dexamethasone-21-sodium phosphate can react with sulfite hydrogen sodium to produce C-1 sulphonation at ring A, which is a reaction on , -unsaturated ketones.

48. The SAR of Dexamethasone Double bond between C1 and C2 increases activity of Glucocorticoid, not that of mineralocorticoid Only β-hydroxyl has activity αhydroxyl, α-methyl , β-methyl decrease Mineralocorticoid activity, α-hydroxyl lower Glucocorticoid activity; α-methyl and β-methyl has no influence on Glucocorticoid activity. α-fluorine will increase activity of Glucocorticoid and Mineralocorticoid. α-methyl has no effect on activity, but α- fluorine will increase Glucocorticoid activity.

49. Modification at C-9 position • 9-Fluorin hydrocortisone is the first famous cortical hormone, which was also discovered by chance. • Its anti-inflammation activity was 10 times stronger than cortisol.

50. Modification at C-16 position • Introducing fluorin at C-9 with other groups at C-16 at same time will decrease effect of water and sodium retention. • 16-Methyl Hydrocortisone increase the activity and stability.