雄性激素和蛋白同化激素（ppt58）课件

Chapter 11 Hormones（2） PeiPei Yu Yu College of Pharmacy College of Pharmacy JinanJinan University University 1 3.Steroid Hormones 3.1 Steroid Estrogen 3.1 Steroid Estrogen ( (雌激素雌激素) ) 3.2 Non-Steroidal Estrogen l Substitution on ring A l Fused rings of ring A l No anabolic hormones without male activity . A 19 6 Common Male Hormones and Anabolic Hormones 7 Testosterone Propionate(丙酸睾酮) l Chemical name： 17-Hydroxyandrost-4-en-3-one propionate 17 3 4 8 Structure of Testosterone Propionate lTestosterone is a natural male hormones. Separated from male cow testis(睾丸) in 1935. lIt is 4-3-ketone and 17-hydroxyl compound, and here it is propionate. lUV absorption. 9 Absorption and Pharmacokinetics lBy oral Testosterone cannot be absorbed in gastrointestinal tract, but Testosterone Propionate oil solution has prolonged effect in vivo because it can be hydrolyzed and release Testosterone slowly. lTestosterone propionate Pro-drug. 10 Biotransformation lThe ratio of activity: Dihydrotestosterone ：Testosterone ： 4-Androstenedione(雄烯二酮) = 150：100 ：10 Dihydrotestosterone 4 Androstenedione 5-Reductase 17 - dehydrogenase Testosterone 11 Analogues of Testosterone The advantage of 17-methyl analogue: lrapid oral absorption, lfine bioavailability, lcan not be decomposed in liver. valerate undecylenate Prolonged effect. 12 Synthesis of Testosterone Dehydrotestosterone Oppenauer 13 3.4 Progestogen Hormone(孕激素) l Progesterone(黄体酮) and 17- hydroxy-progesterone are natural progestogens (孕激素). l Use together with estrogen hormones to keep female reproductive cycle and physiological character. l The preparations of progestogen hormones combined with estrogen hormones are used as oral contraception agents(口服药避孕药). l Offset side-effects in estrogen replacement therapy. 14 Progesterone（黄体酮） lChemical name : Pregn-4-ene-3,20-dione 15 Structure features Differences of structure Progesterone17-acetyl Testosterone17-hydroxyl C-21-Steroids with 4-3-ketone Testosterone (睾酮)Progesterone (黄体酮) 16 17-Substitute Progesterone （ Oral ） lThe first effective oral Progesterone drug is not derived from Progesterone, but a Testostrone analogue Ethisterone (炔孕酮). lWhen 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. 17 lThen 17-Hydroxyprogesterone was found during biosynthesis studies of cortical hormone. The activity of its acetate is only 1% of Norethisterone (炔诺酮). l17-Hydroxyprogesterone Caproate(己酸酯) has a prolonged activity, which oil injection can be used once a month . R= -CH3 hydroxyprogesterone acetate R= -C5H11 hydroxyprogesterone caproate No methyl 18 Medroxyprogesterone Acetate (醋酸甲羟孕酮) lChemical name: (6 )-17-Hydroxy-6-methylpregn-4-ene-3, 20-dione acetate 19 Metabolism of Progesterone Activity are lessened! 20 lThe C-6 analogues Oral Potent Progestin(黄体激素) 6 6 6 21 Levonorgestrel(左炔诺孕酮) lChemical name: D-(-) 17-Ethynyl-17- hydroxy-18-methyl-estro-4-en-3-one 3.5 Steroid Contraceptive agents3.5 Steroid Contraceptive agents( (避孕药避孕药) ) 22 l Chemical structure of Levonorgestrel is similar as Norethisterone (炔诺酮) except C-13 ethyl substitution. l Levonorgestrel(左炔诺孕酮)is the active configuration of the drug, while Dextronorgestrel (右炔诺孕酮) has no effect . D L No methyl 23 Synthesis of Levonorgestrel 24 Mifepristone（米非司酮） lChemical name: 11-4-(Dimethylamino)-phenyl-17-hydroxy-17-(1-propynyl)estra-4, 9-dien-3-one; 3.6 Anti-3.6 Anti-progestogenprogestogen（孕激素拮抗剂） 25 Hormone, its excitomotor and antagonist (激素、激动剂和拮抗剂) pregnancy (hormone antagonist) estrogen (hormone antagonist) Hormones synthesized excitomotor Hormone antagonist 26 Structure feature lCompare with Norethisterone(炔诺酮): C-9 ene 11 -4-(dimethylamino)-phenyl 17 propyne 27 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). l Medical termination of intrauterine pregnancies(子宫 内妊娠)of up to 49-65 days gestation(妊娠). l Softening and dilatation of the cervix(宫颈扩张术) prior to mechanical cervical dilatation for pregnancy termination. l Labor induction in fetal death in utero(宫内死胎). 28 SAR of Mifepristone acetyl phenyl group can increase activity, while short fatty series will turn inhibitor to excitant. If substitute moved to o- or m- position, it will influence on double bond forming to lower drug activity Any substitute has no the activity. Any substitute will decrease the activity. Increase oral activity . - methyl, it will turn inhibitor to excitant. methyl, methanol, or ester cant change anti- corticosteroids activity . 29 Metabolism of Mifepristone N-demethyl N-dedimethyl Propynyl hydroxy 30 Synthesis of Mifepristone From Norethisterone, 8 steps31 1Mineralcorticoids（盐皮质激素）： Oxygen atoms do not exist at C-11 and C-17 at the same time. Aldosterone(醛甾酮) , Deoxycorticosterone(去氧皮质酮) 2Glucocorticoids（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) Classification of adrenocorticoids 3.7 3.7 AdrenocorticoidsAdrenocorticoids( (肾上腺皮质激素肾上腺皮质激素) ) 32 Main Natural Adrenocorticoids 11 17 Glucocorticoids Mineralcorticoids 33 Structural of Adrenocorticoids(肾上腺皮质激素) lPregnane backbone with 4-3, 20-di-one; 11,17, 21- hydroxyls. 11 17 34 Mineralocorticoids(盐皮质激素) lAldosterone (醛甾酮) and deoxycorticosterone(去氧皮质酮). lMineralocorticoids can regulate water and salt metabolism and keep the electrolyte balance in vivo, but it isnt used in clinic widely. lIts metabolism antagonists is used as hydragogues(水泻剂). Aldosterone (醛甾酮) 35 Glucocorticoids(糖皮质激素) lMost of corticoids are Glucocorticoids. lGlucocorticoids are important drugs. lThey have direct relationship with metabolism of sugar, fat, protein and body growth. lGlucocorticoids still keep influence on metabolism of water and salt more or less. Hydrocortison e (氢化可的松) 36 Hydrocortisone(氢化可的松) lChemical name: 11, 17, 21-Trihydroxypregn-4-ene-3, 20-dione 37 lEndogenous（内源的）Hydrocortisone is biosynthesized from cholesterol（胆固醇）via 17-hydroxyl progesterone（ 17-羟基黄体酮）by enzyme catalysis . 17-Hydroxyl-Progesterone BiosynthesisBiosynthesis 38 Metabolism 4, 3-酮被还原C-20侧链断裂 4, 3-ketone are reducedC-20 side-chain is cut down 20 39 How to modify the Glucocorticoids? Modification at C-21. Modification at C-1. 40 Modification at C-21 lOnly C-21 hydroxyl can be esterified, other hydroxyl cant 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 41 Hydrocortisone C-21 esterified analogues Drug NameSubstituent group 42 Modification at C1 lHydroprednisone 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. lIts anti-inflammation activity is 4 times of the leading compound while its sodium retention (钠潴留) activity is not changed. 43 Dexamethasone Acetate(醋酸地塞米松) lChemical name: 9-Fluoro-11, 17, 21-trihydroxypregna-16-methylpregna-1, 4-diene-3,20- dione-21-acetate. 44 Use of Dexamethasone l Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid hormones. l It acts as an anti-inflammatory and immunosuppressant (免疫抑制剂). l Its potency is about 20-30 times that of hydrocortisone (氢化可的松) and 4-5 times of prednisone(强的松). l Shock: 4 to 8 mg intravenously initially, repeat if necessary to a total dose of 24 mg. l 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. 45 Structure feature lAll substituents on the pregnane(孕甾烷) backbone. Most important! 46 Reaction with sodium sulfite lDexamethasone-21-sodium phosphate can react with sulfite hydrogen sodium to produce C-1 sulphonation at ring A, which is a reaction on , -unsaturated ketones. 47 The SAR of Dexamethasone Double bond between C1 and C2 increases activity of Glucocorticoid, not that of mineralocorticoid -methyl has no effect on activity, but - fluorine will increase Glucocorticoid activity. Only -hydroxyl has activity hydroxyl, -methyl , -methyl decrease Mineralocorticoid activity, - hydroxyl lower Glucocorticoid activity; -methyl and -methyl has no influence on Glucocorticoid activity. -fluorine will increase activity of Glucocorticoid and Mineralocorticoid. 48 Modification at C-9 position l9-Fluorin hydrocortisone is the first famous cortical hormone, which was also discovered by chance. lIts anti-inflammation activity was 10 times stronger than cortisol. 49 Modification at C-16 position lIntroducing fluorin at C-9 with other groups at C-16 at same time will decrease effect of water and sodium retention. l16-Methyl Hydrocortisone increase the activity and stability. 50 Modification at C-6 position lIntroducing fluorin at C-6 can prevent it from oxidation. lIt can only be used in the form of external preparation as anti-anaphylaxis(过敏反应)of skin. 51 Stabilit