Steroids Overall Organization of the Lecture Series Structure

Steroids Overall Organization of the Lecture Series Ö Structure, Nomenclature, Conformation, Configuration Ö Anti-Hyperlipidemic Agents Ö Androgens Ö Estrogens and Progestins Ö Anti-inflammatory Steroids and Salt Retaining Agents 10/27/2020 MEDC 603 Steroids 1

Examples of Steroid-based Drugs in Use Today Male Sex Hormone Female Sex Hormone Anti-inflammatory Agent Congested Heart Symptoms 10/27/2020 MEDC 603 Steroids 2

Functional Classification of Steroids Ö Anabolic Steroids - Interact with androgen receptor; enhance muscle mass/athlete’s performance; male sex hormones Ö Glucocorticoids - regulate metabolism and immune function; anti-inflammatory activity Ö Mineralocorticoids - maintain blood volume and renal excretion Ö Progestins - Development of female sex organs and characteristics Ö Phytosteroids - Plant steroids Ö Ergosteroids - Steroids of the fungi; vitamin D related 10/27/2020 MEDC 603 Steroids 3

Structures of Steroids Structure and Nomenclature of the Steroid Nucleus CH 3 21 20 CH 3 C A 10/27/2020 MEDC 603 Steroids B D 22 23 26 25 24 27 4

Configurational Isomers of Steroids Fusion points between rings A B trans- configuration 10/27/2020 MEDC 603 Steroids A B cis- configuration 5

Configurational Isomers of Steroids Fusion points between rings C A D B 3 fusion points 23 isomers = 8 10/27/2020 MEDC 603 Steroids 6

Configurational Isomers of Steroids Three dimensional structure of three most common isomers trans-trans-trans cis-trans-trans cis-trans-cis 10/27/2020 MEDC 603 Steroids 7

Nomenclature of Steroids a- and b- configuration and numbering 10/27/2020 MEDC 603 Steroids 8

Nomenclature of Steroids a- and b- configuration and numbering 10/27/2020 MEDC 603 Steroids 9

Nomenclature of Steroids Number of Nuclear Positions and Steroid Classification C-27 skeleton … Cholestanes C-19 skeleton … Androstanes 10/27/2020 C-24 skeleton … Cholanes C-21 skeleton … Pregnanes C-18 skeleton … Estranes MEDC 603 Steroids 10

Nomenclature of Steroids Usage of ‘Nor’ terminology C-27 skeleton … Cholestanes C-19 skeleton … Androstanes 10/27/2020 18 -Nor C-27 skeleton … 18 -nor cholestane 19 -Nor C-19 skeleton … 19 -nor androstane MEDC 603 Steroids 11

Anti-Hypercholesterolemic Agents Ö Biosynthesis and Metabolism of Cholesterol Ö What is arteriosclerosis? - Link between arteriosclerosis and cholesterol Ö Lipoproteins particles - Structure and classification of lipoprotein particles Ö Hyperlipidemias - Types and overall strategy to control hyperlipidemias Ö Anti-hyperlipidemic Agents - Classes Ö Statins Ö Fibrates Ö Bile Acid Sequestrants Ö Nicotinic Acid Ö Ezetimibe 10/27/2020 MEDC 603 Steroids 12

Biosynthesis of Cholesterol O CH 3 -C-SCo. A -OOC-CH O 2 -C-CH 2 -C-SCo. A OH 3 -hydroxy-3 -methyl-glutaryl-Co. A acetyl coenzyme A HMG Co. A reductase CH 3 -OOC-CH 2 -CH 2 -OH OH mevalonate cholesterol 10/27/2020 MEDC 603 Steroids 13

Metabolism of Cholesterol 10/27/2020 MEDC 603 Steroids 14

Arteriosclerosis is excessive formation and deposition of endogeneous products from blood. In 1984 a 1% drop in serum cholesterol was found to reduce the risk to coronary heart disease (CHD) by nearly 2%. 10/27/2020 MEDC 603 Steroids 15

Lipoprotein Particles Structure 10/27/2020 MEDC 603 Steroids 16

Lipoprotein Particles Classification of lipoprotein particles Composition Density Size Chylomicrons TG >> C, CE Low Large VLDL TG > CE IDL CE > TG LDL CE >> TG HDL CE > TG High Small 10/27/2020 MEDC 603 Steroids 17

Transport of Lipoprotein Particles 10/27/2020 MEDC 603 Steroids 18

Hyperlipidemia Types of hyperlipidemias I IIa IIb III IV V N- N- N- Lipids Cholesterol N- Triglycerides N N- Lipoproteins Chylomicrons VLDL N N- N- LDL N- HDL N = normal, 10/27/2020 N N = increase; = decrease; N N = slight increase; MEDC 603 Steroids N= slight decrease 19

Strategy for Controlling Hyperlipidemia STATINS Biosynthesis Diet HMG Co. A reductase Ezetimibe LDL-R Cellular Cholesterol Serum Cholesterol Conversion to hormones within cells or storage as granules Bile Acids Re-absorption Intestine Feces 10/27/2020 BILE ACID SEQUESTRANTS Lipoprotein catabolism MEDC 603 Steroids FIBRATES 20

Anti-hyperlipidemic Drugs - Statins R R R 10/27/2020 R MEDC 603 Steroids 21

Anti-hyperlipidemic Drugs - Statins Atorvastatin Cerivastatin Rosuvastatin 10/27/2020 MEDC 603 Steroids Fluvastatin Pitavastatin 22

Anti-hyperlipidemic Drugs - Statins Rationale – competitive binding For example, Mevastatin Lovastatin Simvastatin 10/27/2020 For example, Fluvastatin Atorvastatin Cerivastatin MEDC 603 Steroids HMG Co. A substrate 23

Anti-hyperlipidemic Drugs - Statins Pharmacokinetic properties of statins – case of cerivastatin Bioavail. Dosage (mg) Protein Binding Metabolites Atorvastatin ~14% 10 – 80 >98% Active Cerivastatin ~60% 0. 2 – 0. 3 >99% Active Fluvastatin ~24% 10 – 80 98% Active Lovastatin ~5% 10 – 80 >95% Pravastatin ~17% 10 – 40 ~50% Simvastatin ~5% 10 - 80 ~95% Typically all statins possess side effects. The most dominant side effect, cited in the withdrawal of cerivastatin, is rhabdomyolysis (lysis of rhabdomyose) or weakening of skeletal muscles. 10/27/2020 MEDC 603 Steroids 24

Anti-hyperlipidemic Drugs - Fibrates • • • Older generation drugs; introduced in 1981 Second most useful anti-hyperlipidemic drugs Primarily decrease serum triglycerides Increase lipoprotein catabolism; increase TG usage by the body Most used in Type III, IV and V hyperlipidemias 10/27/2020 MEDC 603 Steroids 25

Anti-hyperlipidemic Drugs – Bile Acid Sequestrants • • • Anion exchange resins Water insoluble and inert to digestive enzymes Not absorbed through the GI tract Positively charged nitrogens sequester bile acid re-absorption Lower serum LDL levels Most useful in type IIa and IIb hyperlipidemias 10/27/2020 MEDC 603 Steroids 26

Anti-hyperlipidemic Drugs – Nicotinic Acid • • Administered in large doses (0. 5 to 6 grams daily) Reduces triglycerides and total cholesterol Increases biliary secretion of cholesterol, but not bile acids Useful in Type IIa, IIb, III, IV and V hyperlipidemias 10/27/2020 MEDC 603 Steroids 27

Anti-hyperlipidemic Drugs – Ezetimibe • • Approved in October 2002 Reduces serum LDL, TC, and TG and increases HDL Prevents the absorption of cholesterol from diet Useful in Type IIa, IIb, III, IV and V hyperlipidemias 10/27/2020 MEDC 603 Steroids 28

Androgenic Steroids Overall Organization of the Topic Ö Overall mechanism of steroid hormone action Ö Structure of male sex hormones - Testosterone, androstendione, and 5 a-dihydrotestosterone Ö Nomenclature of androgenic steroids Ö Physiological activities - Androgenic and anabolic activities Ö Biosynthesis and metabolism of testosterone Ö Structure activity relationships - Generalizations Ö Androgen antagonists - Finasteride, danazol, bicalutamide and flutamide 10/27/2020 MEDC 603 Steroids 29

Steroid Hormones Overall Mechanism of Steroid Hormone Action (extracellular) (intranuclear) dimerization A DN (intracellular) transcription translation Intracellular effects proteins extracellular effects 10/27/2020 MEDC 603 Steroids 30

Androgenic Steroids Structure and Nomenclature Testosterone (17 b-hydroxy-androst-4 -en-3 -one) 3 D-structure Androstendione (Andro) (androst-4 -en-3, 17 -dione) 5 a-Dihydro-testosterone (17 b-hydroxy-5 b-androstan-3 -one) 3 D-structure 10/27/2020 MEDC 603 Steroids 31

Androgenic Steroids – Physiological Activities Primarily two activities – Androgenic and Anabolic Androgenic Activity • • Growth and development of male sex organs Important for male sex drive and performance Development of secondary sexual characteristics Important role in spermatogenesis Anabolic Activity • • Development of muscle mass Reverse catabolic or tissue-depleting processes 10/27/2020 MEDC 603 Steroids 32

Androgenic Steroids - Physiological Activities Andro is available over the counter!! 10/27/2020 MEDC 603 Steroids 33

Biosynthesis and Metabolism of Testosterone Cholesterol Other metabolites 10/27/2020 Pregnenolone Testosterone 5 a-DHT Androstendione MEDC 603 Steroids 34

Structure Activity Relationships in Androgens Anabolic Testosterone (injectable) Androgenic 1 1 Testosterone 1 esters (injectable) 1 R = COCH 2 CH 3 propionate = CO(CH 2)5 CH 3 enanthate = COCH 2(C 5 H 9) cypionate 10/27/2020 MEDC 603 Steroids 35

Structure Activity Relationships in Androgens Anabolic 17 a-methyl Testosterone (oral) Fluoxymesterone (oral) 10/27/2020 MEDC 603 Steroids 1 1 Androgenic 1 1 36

Structure Activity Relationships in Androgens Anabolic Nandrolone (injectable) 2. 5 Oxymetholone (oral) 10/27/2020 MEDC 603 Steroids 2. 5 Androgenic 1 1 37

Structure Activity Relationships in Androgens Anabolic Stanozolol (oral) 3 Dromostanolone (oral) 10/27/2020 MEDC 603 Steroids Androgenic 1 4 1 38

Structure Activity Relationships in Androgens 17 a-methyl testosterone (10 -50 mg/day) Ethylestrenol (4 mg/day) Oxandrolone (5 -10 mg/day) Methenolone acetate (20 mg /wk) Norethandrolone 10 -30 mg/day 10/27/2020 Chlorotestosterone acetate (20 mg / wk) MEDC 603 Steroids 39

Androgens Antagonists Danazol (endometriosis) Finesteride (baldness) Bicalutamide (prostate cancer) 10/27/2020 Flutamide (prostate cancer) MEDC 603 Steroids 40

Female Sex Hormonal Steroids Overall Organization of the Topic Ö Structure and nomenclature - Estradiol, estrone, estriol, and progesterone Ö Biosynthesis and metabolism of estradiol and progesterone Ö Synthetic estrogens - Schuler’s hypothesis Ö Estrogen antagonists - clomiphene and tamoxifen Ö Synthetic progestins Ö Progesterone antagonists 10/27/2020 MEDC 603 Steroids 41

Estrogenic Steroids Structure and Nomenclature of Natural Estrogens Estradiol intramuscular 100% estr-1, 3, 5 -triene 3, 17 b-diol 10/27/2020 Estrone intramuscular 33% 3 -hydroxy-estr-1, 3, 5 -triene-17 -one MEDC 603 Steroids Estriol oral 1. 6% estr-1, 3, 5 -triene 3, 16 a, 17 b-triol 42

Progesterone (Progest-4 -ene-3, 20 -dione) 10/27/2020 MEDC 603 Steroids 43

Female Sex Steroids Physiological Activity of Natural Estrogens • • • Reproduction and development of female sex organs Role in ovulation and pregnancy Role in bone density modulation Physiological Activity of Progesterone • • • Maintenance of Pregnancy Inhibition of follicular maturation and ovulation Prevention of spontaneous uterine contractions 10/27/2020 MEDC 603 Steroids 44

Biosynthesis and Metabolism of Estradiol and Progesterone cholesterol estriol pregnenolone testosterone estradiol conjugation to glucuronides, sulfates, etc…. 10/27/2020 MEDC 603 Steroids 45

Synthetic Estrogenic Estradiol look-alikes …. . agonists 10/27/2020 MEDC 603 Steroids 46

Synthetic Estrogenic Diethyl-Stilbestrols (DES) Ethinyl-estradiol R = H Mestranol R = CH 3 Diethylstilbestrol Chlorotrianisene Dienestrol 10/27/2020 MEDC 603 Steroids 47

Synthetic Estrogenic Schuler’s Hypothesis for Synthetic Estrogens 10/27/2020 MEDC 603 Steroids 48

Synthetic Estrogenic 10/27/2020 MEDC 603 Steroids 49

Estrogen Antagonists Triphenylethylene Derivatives – Inverse Agonists Chlorotrianisene (estrogenic) 10/27/2020 MEDC 603 Steroids 50

Selective Estrogen Receptor Modulators (SERM) – tissue specific activity …. Estrogenic for bone growth; antiestrogenic for uterine endometrial growth 10/27/2020 MEDC 603 Steroids 51

Predict the Metabolism of Progesterone ? ? 5 b-metabolite Progesterone ? ? 6 a-hydroxy progesterone 10/27/2020 20 a/b-hydroxy metabolite MEDC 603 Steroids 52

Typical Progesterone Agonists Derivatize ring D Progesterone 17 a-hydroxy progesterone caproate Derivatize rings A & D Medroxyprogesterone acetate 10/27/2020 Megestrol acetate MEDC 603 Steroids Chlormadinone acetate 53

Unusual Progesterone Agonists Testosterone Derivatives Ethisterone Dimethisterone 19 -Nor-testosterone Derivatives Norethisterone 10/27/2020 Norethindrone Norgestimate MEDC 603 Steroids Norgestrel 54

Progesterone Antagonist Mifepristone 10/27/2020 Onapristone MEDC 603 Steroids 55

Adrenocorticoids Steroidal hormones synthesized by the adrenal glands An inner medulla, which is a source of the catecholamines epinephrine and norepinephrine. An outer cortex, which secretes several classes of steroid hormones (glucocorticoids and mineralocorticoids, plus a few others). 10/27/2020 MEDC 603 Steroids 56

Adrenocorticoids Hydrocortisone (11 b, 17 a, 21 -trihydroxy-pregn-4 -ene-3, 20 -dione) Hemi-acetal form Aldehyde-alcohol form Aldosterone (11 b, 21 -dihydroxy-pregn-4 -ene-3, 18, 20 -trione) 10/27/2020 MEDC 603 Steroids 57

Adrenocorticoids Biological Activities 1. Glucocorticoid Activity 1. 1 Effects on Metabolism 1. 1. 1 Stimulation of gluconeogenesis, particularly in the liver 1. 1. 2 Mobilization of amino acids from extrahepatic tissues 1. 1. 3 Inhibition of glucose uptake in muscle and adipose tissue 1. 1. 4 Stimulation of fat breakdown in adipose tissue 1. 2 Effects on Inflammation and Immune Function 1. 2. 1 Anti-inflammatory properties 1. 2. 2 Immunosuppressive properties 1. 3 Other Effects of Glucocorticoids 1. 3. 1 Multiple effects on fetal development (promote maturation of the lung) 1. 3. 2 Miscellaneous effects (Excessive glucocorticoid levels affect many systems, e. g. , inhibition of bone formation, suppression of calcium absorption and delayed wound healing. ) 2. Mineralocorticoid Activity 2. 1 Effect on Electrolytes 2. 1. 1 Increased re-absorption of sodium 2. 1. 2 Increased renal excretion of potassium 2. 2 Effect on Water 2. 2. 1 Increased re-absorption of water 10/27/2020 MEDC 603 Steroids 58

Adrenocorticoids Disease States Addison's disease: Affects about 1 in 100, 000 people; caused by adrenal insufficiency (90%); typical by auto-immune disorders; both cortisol and aldostertone hormones are lacking. Cushing's disease: Affects about 10 to 15 million people / yr; caused by adrenal hyper-activity (cortisol); typical because of tumor growth exposure to prednisone for asthma, rheumatoid arthritis, lupus or other inflammatory diseases 10/27/2020 Conn's syndrome: May affect 15% of patients with high blood pressure; caused by hyper production of aldosterone; inability of adrenal cortex to carry out 17 a-hydroxylation; hypertension, loss of potassium in the urine, muscle weakness and passing of large volumes of urine (polyuria) MEDC 603 Steroids 59

Biochemical Mechanism of Action Cortisol Anti-inflammatory Action Receptor Lipocortin e s a p i ol h sp o Ph A 2 Aldosterone Mineralocorticoid Action Receptor Aldosteroneinduced protein Prostaglandins leucotrienes Cell membrane phospholipids 10/27/2020 Regulates Na+-K+-ATPase Pump Na+ Influx MEDC 603 Steroids 60

Metabolism of Adrenocorticoids 10/27/2020 MEDC 603 Steroids 61

Structure-Activity Relationships Antiinflammatory activity 10/27/2020 Saltretaining activity Plasma half life Hydrocortisone 1 1 120 m Cortisone 0. 8 30 m Prednisone 4 MEDC 603 Steroids 1 60 m 62

Structure-Activity Relationships Antiinflammatory activity 10/27/2020 Saltretaining activity Prednisone 4 1 Prednisolone 4 0. 6 MEDC 603 Steroids Plasma half life 60 m 115 -212 m 63

Structure-Activity Relationships Antiinflammatory activity Prednisolone 6 a-methyl prednisolone Triamcinolone 10/27/2020 Saltretaining activity 4 0. 6 4 0 5 MEDC 603 Steroids Plasma half life 115 -212 m 78 -188 m 0 200+ m 64

Structure-Activity Relationships Antiinflammatory activity Dexamethasone Betamethasone 10/27/2020 30 35 MEDC 603 Steroids Saltretaining activity 0 Plasma half life 110 -210 m 0 300+ m 65

Structure-Activity Relationships Antiinflammatory activity Saltretaining activity Plasma half life 0. 2 800 30 m 11 -deoxy corticosterone 0 40 60 m Fludrocortisone 10 Aldosterone 10/27/2020 MEDC 603 Steroids 800 300+ m 66