Steroids Overall Organization of the Lecture Series Introduction - Structure, Nomenclature, Conformation, Configuration Hypercholesterolemia - Cholesterol, Anti-hyperlipidemic Agents Male Sex Hormones - Androgens Female Sex Hormones - Estrogens and Progestins Adrenocorticoids - Anti-inflammatory and Salt Retaining Agents 11/9/2018 MEDC 603 Steroids

Examples of Steroid-based Drugs in Use Today Male Sex Hormone Female Sex Hormone Congested Heart Symptoms Anti-inflammatory Agent 11/9/2018 MEDC 603 Steroids

Structures of Steroids Structure and Nomenclature of the Steroid Nucleus 18 CH3 12 15 16 17 19 11 13 A B C D 1 8 9 2 14 10 3 6 7 5 4 11/9/2018 MEDC 603 Steroids

Structures of Steroids Structure and Nomenclature of the Steroid Side-chain 21 22 20 26 27 23 24 25 11/9/2018 MEDC 603 Steroids

Configurational Isomers of Steroids Fusion points between rings A B A B trans- configuration cis- configuration 11/9/2018 MEDC 603 Steroids

Configurational Isomers of Steroids Fusion points between rings A B C D 3 fusion points  23 isomers = 8 11/9/2018 MEDC 603 Steroids

Configurational Isomers of Steroids Three dimensional structure of three most common isomers trans-trans-trans cis-trans-trans cis-trans-cis 11/9/2018 MEDC 603 Steroids

Nomenclature of Steroids a- and b- configuration and numbering 11/9/2018 MEDC 603 Steroids

Nomenclature of Steroids a- and b- configuration and numbering 11/9/2018 MEDC 603 Steroids

Biosynthesis and Metabolism of Cholesterol CH3-C-SCoA -OOC-CH2-C-CH2-C-SCoA O OH CH3 acetyl coenzyme A 3-hydroxy-3-methyl-glutaryl-CoA HMG CoA reductase cholesterol -OOC-CH2-C-CH2-CH2-OH OH CH3 mevalonate 11/9/2018 MEDC 603 Steroids

Biosynthesis and Metabolism of Cholesterol liver various tissues Bile Acids (cholic acid, desoxy cholic acid, etc.) Hormones (testosterone, progesterone cortisol, estradiol, etc.) 11/9/2018 MEDC 603 Steroids

Anti-Hypercholesterolemic Agents Overall Organization of the Topic What is arteriosclerosis? - Link between arteriosclerosis and cholesterol Lipoproteins particles - Structure and classification of lipoprotein particles Hyperlipidemias - Types and overall strategy to control hyperlipidemias Anti-hyperlipidemic Agents - Classes Statins Fibrates Bile Acid Sequestrants Nicotinic Acid Ezetimibe 11/9/2018 MEDC 603 Steroids

Arteriosclerosis 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%. 11/9/2018 MEDC 603 Steroids

Lipoprotein Particles Structure 11/9/2018 MEDC 603 Steroids

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 High Small 11/9/2018 MEDC 603 Steroids

Hyperlipidemia Types of hyperlipidemias I IIa IIb III IV V Lipids Cholesterol N- Triglycerides N Lipoproteins Chylomicrons VLDL LDL HDL N = normal, = increase; = decrease; = slight increase; = slight decrease 11/9/2018 MEDC 603 Steroids

Strategy for Controlling Hyperlipidemia STATINS Diet Biosynthesis HMG CoA reductase Ezetimibe Cellular Cholesterol LDL-R Serum Cholesterol Bile Acids Intestine Re-absorption Lipoprotein catabolism Conversion to hormones within cells or storage as granules Feces BILE ACID SEQUESTRANTS FIBRATES 11/9/2018 MEDC 603 Steroids

Anti-hyperlipidemic Drugs - Statins Inhibit the rate limiting step in cholesterol biosynthesis (HMG CoA reductase) Lower total cholesterol and LDL Competitive inhibitors with affinity higher than the substrate (HMG CoA) Most used in Type IIa and IIb hyperlipidemias R trans-trans-trans cis-trans-trans cis-trans-cis 11/9/2018 MEDC 603 Steroids

Anti-hyperlipidemic Drugs - Statins 11/9/2018 MEDC 603 Steroids

Anti-hyperlipidemic Drugs - Statins Rationale – competitive binding For example, Mevastatin Lovastatin Simvastatin Fluvastatin Atorvastatin Cerivastatin HMG CoA substrate 11/9/2018 MEDC 603 Steroids

Anti-hyperlipidemic Drugs - Statins Pharmacokinetic properties of statins – case of cerivastatin Bioavailabilty Dosage (mg) Protein Binding Metabolites Atorvastatin ~14% 10 – 80 >98% Active Cerivastatin ~60% 0.2 – 0.3 >99% Fluvastatin ~24% 98% Lovastatin ~5% >95% Pravastatin ~17% 10 – 40 ~50% Simvastatin 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. 11/9/2018 MEDC 603 Steroids

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 11/9/2018 MEDC 603 Steroids

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 11/9/2018 MEDC 603 Steroids

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 11/9/2018 MEDC 603 Steroids

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 11/9/2018 MEDC 603 Steroids

Androgenic Steroids Overall Organization of the Topic Overall mechanism of steroid hormone action Structure of male sex hormones - Testosterone, androstendione, and 5a-dihydrotestosterone Nomenclature of androgenic steroids Physiological activities - Androgenic and anabolic activities Biosynthesis and metabolism of testosterone Structure activity relationships - Generalizations Androgen antagonists - Finasteride, danazol, bicalutamide and flutamide 11/9/2018 MEDC 603 Steroids

Steroid Hormones Overall Mechanism of Steroid Hormone Action (intracellular) (intranuclear) proteins Intracellular effects extracellular effects transcription translation dimerization DNA (extracellular) 11/9/2018 MEDC 603 Steroids

Androgenic Steroids Structure and Nomenclature Testosterone Androstendione (Andro) (17b-hydroxy-androst-4-en-3-one) 3D-structure (androst-4-en-3,17-dione) 5a-Dihydro-testosterone (17b-hydroxy-5b-androstan-3-one) 3D-structure 11/9/2018 MEDC 603 Steroids

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 11/9/2018 MEDC 603 Steroids

Androgenic Steroids - Physiological Activities Andro is available over the counter!! 11/9/2018 MEDC 603 Steroids

Biosynthesis and Metabolism of Testosterone Cholesterol Pregnenolone Testosterone Other metabolites 5a-DHT Androstendione 11/9/2018 MEDC 603 Steroids

Structure Activity Relationships in Androgens Anabolic Androgenic Testosterone 1 1 (injectable) Testosterone 1 1 esters (injectable) R = COCH2CH3 propionate = CO(CH2)5CH3 enanthate = COCH2CH2(C5H9) cypionate 11/9/2018 MEDC 603 Steroids

Structure Activity Relationships in Androgens Anabolic Androgenic 17a-methyl Testosterone 1 1 (oral) Fluoxymesterone 1 1 (oral) 11/9/2018 MEDC 603 Steroids

Structure Activity Relationships in Androgens Anabolic Androgenic Nandrolone 2.5 1 (injectable) Oxymetholone 2.5 1 (oral) 11/9/2018 MEDC 603 Steroids

Structure Activity Relationships in Androgens Anabolic Androgenic Stanozolol 3 1 (oral) Dromostanolone 4 1 (oral) 11/9/2018 MEDC 603 Steroids

Structure Activity Relationships in Androgens Generalizations Steroid skeleton is necessary An electronegative (may not be oxygen) at 3 position is required A/B ring fusion should be either trans or presence of a double bond at 4 position Alkyl group (CH3) at 17a-position is necessary for anabolic activity Alkyl group at 17a- confers oral activity 11/9/2018 MEDC 603 Steroids

Androgens Antagonists Danazol (endometriosis) Finesteride (baldness) Bicalutamide (prostate cancer) Flutamide (prostate cancer) 11/9/2018 MEDC 603 Steroids

Estrogenic Steroids Overall Organization of the Topic Structure and nomenclature of natural estrogens - Estradiol, estrone, and estriol Biosynthesis and metabolism of estradiol Synthetic estrogens - Schuler’s hypothesis Estrogen antagonists - clomiphene and tamoxifen 11/9/2018 MEDC 603 Steroids

Estrogenic Steroids Structure and Nomenclature of Natural Estrogens Estradioll Estrone Estriol intramuscular intramuscular oral 100% 33% 1.6% estr-1,3,5-triene- 3,17b-diol 3-hydroxy-estr-1,3,5 -triene-17-one estr-1,3,5-triene- 3,16a,17b-triol 11/9/2018 MEDC 603 Steroids

Biosynthesis and Metabolism of Estradiol cholesterol pregnenolone testosterone estriol estrone estradiol conjugation to glucuronides, sulfates, etc…. 11/9/2018 MEDC 603 Steroids

Synthetic Estrogenic ethinyl-estradiol diethylstilbestrol chlorotrianisene dienestrol 11/9/2018 MEDC 603 Steroids

Synthetic Estrogenic Schuler’s Hypothesis for Synthetic Estrogens 11/9/2018 MEDC 603 Steroids

Synthetic Estrogenic 11/9/2018 MEDC 603 Steroids

Estrogen Antagonists chlorotrianisene clomiphene (estrogenic) (anti-estrogenic) tamoxifen (anti-estrogenic) 11/9/2018 MEDC 603 Steroids

Progestins Overall Organization of the Topic Structure and function of natural progestin - Progesterone Nomenclature of progestational steroids Biosynthesis and metabolism of progesterone Progesterone Agonists Generalizations on Structure-Activity Relationships Progesterone antagonist - RU-486 11/9/2018 MEDC 603 Steroids

Progestins Progest-4-ene-3,20-dione Progesterone 11/9/2018 MEDC 603 Steroids

Inhibits follicular maturation and ovulation Functions of Progesterone Maintains pregnancy Inhibits follicular maturation and ovulation prevents spontaneous uterine contraction 11/9/2018 MEDC 603 Steroids

Progesterone Metabolism Reduction C-20 Reduction C-4, C-3 Reduction C-20 Reduction C-4, C-3 11/9/2018 MEDC 603 Steroids

Progesterone Agonists 1. Derivatization of the 17 - position 17a-hydroxyprogesterone caproate Click here to view the 3D structure of 17-substitution 11/9/2018 MEDC 603 Steroids

Medroxyprogesterone acetate Progesterone Agonists 2. Derivatization of A/B rings Medroxyprogesterone acetate (Oral Activity = 12-25) Megestrol acetate Chlomadinone acetate 11/9/2018 MEDC 603 Steroids

Progesterone Agonists 3. Testosterone Derivatives Ethisterone Dimethisterone Relative Oral Activity = 1 Relative Oral Activity = 12 11/9/2018 MEDC 603 Steroids

Progesterone Agonists 4. 19-Nortestosterone Derivatives Norethindrone Norgestrel Relative Oral Activity = 5-10 11/9/2018 MEDC 603 Steroids

Either a progesterone or a testosterone skeleton Generalizations on Structure-Activity Relationships for Oral Progestational Activity Steroid skeleton Unsaturated A ring Either a progesterone or a testosterone skeleton If testosterone derivative, 17-ethinyl substitution 19-nor substitution is useful 11/9/2018 MEDC 603 Steroids

Hormone Replacement Therapy Osteoporosis Hot Flashes Heart Diseases Cancer Link to Latest on HRT 11/9/2018 MEDC 603 Steroids

Progesterone Antagonist RU-486: Mifepristone 11/9/2018 MEDC 603 Steroids

Adrenocorticoids 11/9/2018 MEDC 603 Steroids

Adrenocorticoids Hydrocortisol Aldosterone (11b,17a,21-trihydroxy- pregn-4-ene-3,20-dione) Aldosterone (11b,21-dihydroxy- pregn-4-ene-3,18,20-trione) 11/9/2018 MEDC 603 Steroids

Adrenocorticoids Addison’s Disease  Disease States Cushing’s Disease Conn’s Syndrome  Disease States 11/9/2018 MEDC 603 Steroids

Adrenocorticoids  Selected Indications Allergic Rhinitis Rheumatoid Arthritis Asthma Multiple Sclerosis Carpal Tunnel Syndrome Dermatitis COPD Osteoarthritis Cystic Fibrosis Temporal Arteritis Gout Psoriasis Herniated Disc Shingles Inflammatory Bowel Disease Tennis Elbow Sinusitis Lupus Erythematosus 11/9/2018 MEDC 603 Steroids

Overall Equilibrium in Aldosterone Opened form hemi-acetal form Aldosterone 11/9/2018 MEDC 603 Steroids

3D structure of hydrocortisol Overall Structure of Adrenocorticoids ~ planar A ring Differences in the substitution pattern 3D structure of hydrocortisol 11/9/2018 MEDC 603 Steroids

Biochemical Mechanism of Action Cortisol Aldosterone Anti-inflammatory Action Mineralocorticoid Action Receptor Receptor Lipocortin Aldosterone- induced protein Phospholipase A2 Cell membrane phospholipids Prostaglandins leucotrienes Regulates Na+-K+-ATPase Pump Na+ Influx 11/9/2018 MEDC 603 Steroids

Metabolism of Adrenocorticoids Reduction C-20 Reduction C-4 Reduction C-3 11/9/2018 MEDC 603 Steroids

at C-3, C-4 and C-20 positions Metabolism of Adrenocorticoids Oxidation C-11 Reduction at C-3, C-4 and C-20 positions 11/9/2018 MEDC 603 Steroids

Structure-Activity Relationships Anti- Salt- Plasma inflammatory retaining half activity activity life Hydrocortisone 1 1 120 m Cortisone 0.8 0.8 30 m 11/9/2018 MEDC 603 Steroids

Structure-Activity Relationships Anti- Salt- Plasma inflammatory retaining half activity activity life Prednisone 4 1 60 m Prednisolone 4 0.6 115-212 m 11/9/2018 MEDC 603 Steroids

Structure-Activity Relationships Anti- Salt- Plasma inflammatory retaining half activity activity life 6a-methyl 4 0 78-188 m prednisolone Triamcinolone 5 0 200+ m 11/9/2018 MEDC 603 Steroids

Structure-Activity Relationships Anti- Salt- Plasma inflammatory retaining half activity activity life Dexamethasone 30 0 110-210 m Betamethasone 35 0 300+ m 11/9/2018 MEDC 603 Steroids

Structure-Activity Relationships Anti- Salt- Plasma inflammatory retaining half activity activity life Aldosterone 0.2 800 30 m 11-deoxy 0 40 60 m corticosterone Fludrocortisone 10 800 300+ m 11/9/2018 MEDC 603 Steroids