1. 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
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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. 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
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4. Structures of Steroids
Structure and Nomenclature of the Steroid Side-chain 21 22 20 26 27 23 24 25
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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
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. Biosynthesis and Metabolism 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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11. Biosynthesis and Metabolism of Cholesterol
liver
various tissues
Bile Acids
(cholic acid, desoxy
cholic acid, etc.)
Hormones
(testosterone, progesterone
cortisol, estradiol, etc.)
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12. 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
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13. 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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14. Lipoprotein Particles
Structure
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15. 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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16. 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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17. 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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18. 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
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19. Anti-hyperlipidemic Drugs - Statins
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20. Anti-hyperlipidemic Drugs - Statins
Rationale – competitive binding
For example,
Mevastatin
Lovastatin
Simvastatin
Fluvastatin
Atorvastatin
Cerivastatin
HMG CoA substrate
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21. 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
~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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22. 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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23. 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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24. 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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25. 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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26. 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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27. Steroid Hormones Overall Mechanism of Steroid Hormone Action
(intracellular)
(intranuclear)
proteins
Intracellular effects
extracellular effects
transcription
translation
dimerization
DNA
(extracellular)
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28. 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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29. 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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30. Androgenic Steroids - Physiological Activities
Andro is available over the counter!!
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31. Biosynthesis and Metabolism of Testosterone
Cholesterol
Pregnenolone
Testosterone
Other metabolites
5a-DHT
Androstendione
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32. 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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33. Structure Activity Relationships in Androgens
Anabolic Androgenic
17a-methyl
Testosterone
(oral)
Fluoxymesterone
(oral)
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34. Structure Activity Relationships in Androgens
Anabolic Androgenic
Nandrolone
(injectable)
Oxymetholone
(oral)
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35. Structure Activity Relationships in Androgens
Anabolic Androgenic
Stanozolol
(oral)
Dromostanolone
(oral)
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36. 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
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37. Androgens Antagonists
Danazol
(endometriosis)
Finesteride
(baldness)
Bicalutamide
(prostate cancer)
Flutamide
(prostate cancer)
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38. 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
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39. Estrogenic Steroids Structure and Nomenclature of Natural Estrogens
Estradioll 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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40. Biosynthesis and Metabolism of Estradiol
cholesterol pregnenolone testosterone
estriol estrone estradiol
conjugation to glucuronides, sulfates, etc….
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41. Synthetic Estrogenic ethinyl-estradiol diethylstilbestrol
chlorotrianisene dienestrol
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42. Synthetic Estrogenic Schuler’s Hypothesis for Synthetic Estrogens
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43. Synthetic Estrogenic
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44. Estrogen Antagonists chlorotrianisene clomiphene
(estrogenic) (anti-estrogenic)
tamoxifen
(anti-estrogenic)
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45. 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
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46. Progestins Progest-4-ene-3,20-dione Progesterone 11/9/2018
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47. Inhibits follicular maturation and ovulation
Functions of Progesterone
Maintains pregnancy
Inhibits follicular maturation and ovulation
prevents spontaneous uterine contraction
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48. Progesterone Metabolism
Reduction C-20
Reduction
C-4, C-3
Reduction C-20
Reduction
C-4, C-3
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49. Progesterone Agonists
1. Derivatization of the 17 - position
17a-hydroxyprogesterone caproate
Click here to view the 3D structure of 17-substitution
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50. Medroxyprogesterone acetate
Progesterone Agonists
2. Derivatization of A/B rings
Medroxyprogesterone acetate
(Oral Activity = 12-25)
Megestrol acetate
Chlomadinone acetate
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51. Progesterone Agonists
3. Testosterone Derivatives
Ethisterone
Dimethisterone
Relative Oral Activity = 1
Relative Oral Activity = 12
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52. Progesterone Agonists
Nortestosterone Derivatives
Norethindrone
Norgestrel
Relative Oral Activity = 5-10
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53. 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
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54. Hormone Replacement Therapy
Osteoporosis
Hot Flashes
Heart Diseases
Cancer
Link to Latest on HRT
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55. Progesterone Antagonist
RU-486: Mifepristone
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56. Adrenocorticoids
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57. Adrenocorticoids Hydrocortisol Aldosterone (11b,17a,21-trihydroxy-
pregn-4-ene-3,20-dione)
Aldosterone
(11b,21-dihydroxy-
pregn-4-ene-3,18,20-trione)
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58. Adrenocorticoids Addison’s Disease  Disease States Cushing’s Disease
Conn’s Syndrome
 Disease States
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59. 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
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60. Overall Equilibrium in Aldosterone
Opened form hemi-acetal form
Aldosterone
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61. 3D structure of hydrocortisol
Overall Structure of Adrenocorticoids
~ planar A ring
Differences in the
substitution pattern
3D structure of hydrocortisol
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62. 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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63. Metabolism of Adrenocorticoids
Reduction C-20
Reduction
C-4
Reduction C-3
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64. 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
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65. Structure-Activity Relationships
Anti Salt Plasma
inflammatory retaining half
activity activity life
Hydrocortisone m
Cortisone m
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66. Structure-Activity Relationships
Anti Salt Plasma
inflammatory retaining half
activity activity life
Prednisone m
Prednisolone m
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67. Structure-Activity Relationships
Anti Salt Plasma
inflammatory retaining half
activity activity life
6a-methyl m
prednisolone
Triamcinolone m
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68. Structure-Activity Relationships
Anti Salt Plasma
inflammatory retaining half
activity activity life
Dexamethasone m
Betamethasone m
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69. Structure-Activity Relationships
Anti Salt Plasma
inflammatory retaining half
activity activity life
Aldosterone m
11-deoxy m
corticosterone
Fludrocortisone m
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