1. Steroids Overall Organization of the Lecture Series
Structure, Nomenclature, Conformation, Configuration
Anti-Hyperlipidemic Agents
Androgens
Estrogens and Progestins
Anti-inflammatory Steroids and Salt Retaining Agents
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2. Examples of Steroid-based Drugs in Use Today
Male Sex
Hormone
Female Sex
Hormone
Congested Heart
Symptoms
Anti-inflammatory
Agent
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3. Functional Classification of Steroids
Anabolic Steroids
- Interact with androgen receptor; enhance muscle mass/athlete’s performance; male sex hormones
Glucocorticoids
- regulate metabolism and immune function; anti-inflammatory activity
Mineralocorticoids
- maintain blood volume and renal excretion
Progestins
- Development of female sex organs and characteristics
Phytosteroids
- Plant steroids
Ergosteroids
- Steroids of the fungi; vitamin D related
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4. Structures of Steroids
Structure and Nomenclature of the Steroid Nucleus
CH3 A B C D 20 21 22 23 24 25 26 27
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5. Configurational Isomers of Steroids
Fusion points between rings
A B
A B
trans- configuration
cis- configuration
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6. Configurational Isomers of Steroids
Fusion points between rings A B C D
3 fusion points  23 isomers = 8
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7. Configurational Isomers of Steroids
Three dimensional structure of three most common isomers
trans-trans-trans
cis-trans-trans
trans-trans-trans
cis-trans-trans
cis-trans-cis
cis-trans-cis
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8. Nomenclature of Steroids
a- and b- configuration and numbering
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9. Nomenclature of Steroids
a- and b- configuration and numbering
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10. Nomenclature of Steroids
Number of Nuclear Positions and Steroid Classification
C-27 skeleton
… Cholestanes
C-24 skeleton
… Cholanes
C-21 skeleton
… Pregnanes
C-19 skeleton
… Androstanes
C-18 skeleton
… Estranes
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11. Nomenclature of Steroids
Usage of ‘Nor’ terminology
C-27 skeleton
… Cholestanes
18-Nor C-27 skeleton
… 18-nor cholestane
C-19 skeleton
… Androstanes
19-Nor C-19 skeleton
… 19-nor androstane
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12. Anti-Hypercholesterolemic Agents
Biosynthesis and Metabolism of Cholesterol
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
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13. Biosynthesis of Cholesterol
CH3-C-SCoA OOC-CH2-C-CH2-C-SCoA O OH
CH3
acetyl coenzyme A hydroxy-3-methyl-glutaryl-CoA
HMG CoA
reductase
cholesterol
-OOC-CH2-C-CH2-CH2-OH OH
CH3
mevalonate
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14. Metabolism of Cholesterol
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15. 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%.
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16. Lipoprotein Particles
Structure
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17. 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
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18. Transport of Lipoprotein Particles
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19. 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
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20. 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
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21. Anti-hyperlipidemic Drugs - Statins
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22. Anti-hyperlipidemic Drugs - Statins
Atorvastatin Cerivastatin Fluvastatin
Rosuvastatin Pitavastatin
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23. Anti-hyperlipidemic Drugs - Statins
Rationale – competitive binding
For example,
Mevastatin
Lovastatin
Simvastatin
Fluvastatin
Atorvastatin
Cerivastatin
HMG CoA substrate
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24. 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%
Fluvastatin
~24%
98%
Lovastatin
~5%
>95%
Pravastatin
~17%
10 – 40
~50%
Simvastatin
~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.
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25. 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
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26. 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
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27. 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
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28. 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
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29. 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
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30. Steroid Hormones Overall Mechanism of Steroid Hormone Action
(intracellular)
(intranuclear)
proteins
Intracellular effects
extracellular effects
transcription
translation
dimerization
DNA
(extracellular)
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31. 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
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32. 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
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33. Androgenic Steroids - Physiological Activities
Andro is available over the counter!!
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34. Biosynthesis and Metabolism of Testosterone
Cholesterol
Pregnenolone
Testosterone
Other metabolites
5a-DHT
Androstendione
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35. Structure Activity Relationships in Androgens
Anabolic Androgenic
Testosterone
(injectable)
Testosterone
esters (injectable)
R = COCH2CH propionate
= CO(CH2)5CH enanthate
= COCH2CH2(C5H9) cypionate
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36. Structure Activity Relationships in Androgens
Anabolic Androgenic
17a-methyl
Testosterone
(oral)
Fluoxymesterone
(oral)
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37. Structure Activity Relationships in Androgens
Anabolic Androgenic
Nandrolone
(injectable)
Oxymetholone
(oral)
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38. Structure Activity Relationships in Androgens
Anabolic Androgenic
Stanozolol
(oral)
Dromostanolone
(oral)
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39. Structure Activity Relationships in Androgens
17a-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
Chlorotestosterone acetate (20 mg / wk)
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40. Androgens Antagonists
Danazol
(endometriosis)
Finesteride
(baldness)
Bicalutamide
(prostate cancer)
Flutamide
(prostate cancer)
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41. Female Sex Hormonal Steroids
Overall Organization of the Topic
Structure and nomenclature
- Estradiol, estrone, estriol, and progesterone
Biosynthesis and metabolism of estradiol and progesterone
Synthetic estrogens
- Schuler’s hypothesis
Estrogen antagonists
- clomiphene and tamoxifen
Synthetic progestins
Progesterone antagonists
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42. Estrogenic Steroids Structure and Nomenclature of Natural Estrogens
Estradiol Estrone Estriol
intramuscular intramuscular oral
100% % %
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
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43. Progesterone Progesterone (Progest-4-ene-3,20-dione) 11/9/2018
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44. 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
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45. Biosynthesis and Metabolism of Estradiol and Progesterone
cholesterol pregnenolone testosterone
estriol estrone estradiol
conjugation to glucuronides, sulfates, etc….
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46. Synthetic Estrogenic Estradiol look-alikes ….. agonists 11/9/2018
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47. Synthetic Estrogenic Diethyl-Stilbestrols (DES)
Ethinyl-estradiol R = H Diethylstilbestrol
Mestranol R = CH3
Chlorotrianisene Dienestrol
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48. Synthetic Estrogenic Schuler’s Hypothesis for Synthetic Estrogens
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49. Synthetic Estrogenic
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50. Estrogen Antagonists Triphenylethylene Derivatives – Inverse Agonists
Chlorotrianisene
(estrogenic)
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51. Selective Estrogen Receptor Modulators (SERM)
– tissue specific activity …. Estrogenic for bone growth; anti-estrogenic for uterine endometrial growth
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52. ?? ?? ?? Predict the Metabolism of Progesterone Progesterone
5b-metabolite ?? ?? ??
6a-hydroxy progesterone
20a/b-hydroxy metabolite
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53. Typical Progesterone Agonists
17a-hydroxy progesterone
caproate
Derivatize ring D
Derivatize rings A & D
Medroxyprogesterone acetate
Megestrol
acetate
Chlormadinone
acetate
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54. Unusual Progesterone Agonists
Testosterone Derivatives
Ethisterone
Dimethisterone
Norethisterone
Norethindrone
Norgestimate
Norgestrel
19-Nor-testosterone Derivatives
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55. Progesterone Antagonist
Mifepristone
Onapristone
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56. Steroidal hormones synthesized by the adrenal glands
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).
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57. Adrenocorticoids Hydrocortisone Aldosterone Hemi-acetal form
(11b,17a,21-trihydroxy-pregn-4-ene-3,20-dione)
Hemi-acetal form
Aldehyde-alcohol form
Aldosterone
(11b,21-dihydroxy-pregn-4-ene-3,18,20-trione)
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58. Adrenocorticoids  Biological Activities 1. Glucocorticoid Activity
1.1 Effects on Metabolism
Stimulation of gluconeogenesis, particularly in the liver
Mobilization of amino acids from extrahepatic tissues
Inhibition of glucose uptake in muscle and adipose tissue
Stimulation of fat breakdown in adipose tissue
1.2 Effects on Inflammation and Immune Function
Anti-inflammatory properties
Immunosuppressive properties
1.3 Other Effects of Glucocorticoids
Multiple effects on fetal development (promote maturation of the lung)
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
Effect on Water
2.2.1 Increased re-absorption of water
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59. Adrenocorticoids  Disease States
 Addison's disease: Affects about 1 in 100,000 people; caused by adrenal in-sufficiency (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
 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 17a-hydroxylation; hypertension, loss of potassium in the urine, muscle weakness and passing of large volumes of urine (polyuria)
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60. 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
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61. Metabolism of Adrenocorticoids
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62. Structure-Activity Relationships
Anti Salt Plasma
inflammatory retaining half
activity activity life
Hydrocortisone m
Cortisone m
Prednisone m
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63. Structure-Activity Relationships
Anti Salt Plasma
inflammatory retaining half
activity activity life
Prednisone m
Prednisolone m
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64. Structure-Activity Relationships
Anti Salt Plasma
inflammatory retaining half
activity activity life
Prednisolone m
6a-methyl m
prednisolone
Triamcinolone m
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65. Structure-Activity Relationships
Anti Salt Plasma
inflammatory retaining half
activity activity life
Dexamethasone m
Betamethasone m
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66. Structure-Activity Relationships
Anti Salt Plasma
inflammatory retaining half
activity activity life
Aldosterone m
11-deoxy m
corticosterone
Fludrocortisone m
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