Steroids

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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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Examples of Steroid-based Drugs in Use Today
Female Sex Hormone
Male Sex Hormone
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Functional Classification of Steroids

• Anabolic Steroids
• - Interact with androgen receptor enhance
  muscle mass/athletes 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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Structures of Steroids
Structure and Nomenclature of the Steroid Nucleus
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Configurational Isomers of Steroids
Fusion points between rings
A B
A B
trans- configuration
cis- configuration
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Configurational Isomers of Steroids
Fusion points between rings
3 fusion points ? 23 isomers 8
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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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Nomenclature of Steroids
a- and b- configuration and numbering
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Nomenclature of Steroids
a- and b- configuration and numbering
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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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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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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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Biosynthesis of Cholesterol
HMG CoA reductase
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Metabolism of Cholesterol
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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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Lipoprotein Particles
Structure
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Lipoprotein Particles
Classification of lipoprotein particles
Composition Density Size

Chylomicrons TG gtgt C, CE Low Large
VLDL TG gt CE
IDL CE gt TG
LDL CE gtgt TG
HDL CE gt TG High Small
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Transport of Lipoprotein Particles
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Hyperlipidemia
Types of hyperlipidemias
I IIa IIb III IV V
Lipids
Cholesterol N- N- N- N-
Triglycerides N N-
Lipoproteins
Chylomicrons N N N N
VLDL N- N- N-
LDL N-
HDL N N N N-
N normal, increase decrease
slight increase slight decrease
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Strategy for Controlling Hyperlipidemia
STATINS
HMG CoA reductase
Ezetimibe
BILE ACID SEQUESTRANTS
FIBRATES
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Anti-hyperlipidemic Drugs - Statins
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Anti-hyperlipidemic Drugs - Statins
Atorvastatin Cerivastatin

Fluvastatin
Rosuvastatin
Pitavastatin
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Anti-hyperlipidemic Drugs - Statins
Rationale competitive binding
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Anti-hyperlipidemic Drugs - Statins
Pharmacokinetic properties of statins case of
cerivastatin
Bioavail. Dosage (mg) Protein Binding Metabolites
Atorvastatin 14 10 80 gt98 Active
Cerivastatin 60 0.2 0.3 gt99 Active
Fluvastatin 24 10 80 98 Active
Lovastatin 5 10 80 gt95
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.
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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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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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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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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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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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Steroid Hormones
Overall Mechanism of Steroid Hormone Action
(extracellular)
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Androgenic Steroids
Structure and Nomenclature
Androstendione (Andro)
Testosterone
(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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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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Androgenic Steroids - Physiological Activities
Andro is available over the counter!!
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Biosynthesis and Metabolism of Testosterone
Testosterone
Cholesterol
Pregnenolone
Androstendione
5a-DHT
Other metabolites
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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
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Structure Activity Relationships in Androgens
Anabolic Androgenic
17a-methyl Testosterone 1
1 (oral)
Fluoxymesterone 1
1 (oral)
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Structure Activity Relationships in Androgens
Anabolic Androgenic
Nandrolone 2.5
1 (injectable)
Oxymetholone 2.5
1 (oral)
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Structure Activity Relationships in Androgens
Anabolic Androgenic
Stanozolol 3
1 (oral)
Dromostanolone 4
1 (oral)
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Structure Activity Relationships in Androgens
Ethylestrenol (4 mg/day)
17a-methyl testosterone (10-50 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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Androgens Antagonists
Danazol (endometriosis)
Finesteride (baldness)
Bicalutamide (prostate cancer)
Flutamide (prostate cancer)
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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
• - Schulers hypothesis
• Estrogen antagonists
• - clomiphene and tamoxifen
• Synthetic progestins
• Progesterone antagonists

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Estrogenic Steroids
Structure and Nomenclature of Natural Estrogens
Estradiol Estrone
Estriol intramuscular
intramuscular
oral 100
33 1.6
3-hydroxy-estr-1,3,5 -triene-17-one
estr-1,3,5-triene- 3,17b-diol
estr-1,3,5-triene- 3,16a,17b-triol
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Progesterone
Progesterone
(Progest-4-ene-3,20-dione)
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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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Biosynthesis and Metabolism of Estradiol and
Progesterone
cholesterol
pregnenolone testosterone
estriol
estrone estradiol
conjugation to glucuronides, sulfates, etc.
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Synthetic Estrogenic
Estradiol look-alikes .. agonists
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Synthetic Estrogenic
Diethyl-Stilbestrols (DES)
Ethinyl-estradiol R H
Diethylstilbestrol Mestranol R CH3
Chlorotrianisene
Dienestrol
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Synthetic Estrogenic
Schulers Hypothesis for Synthetic Estrogens
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Synthetic Estrogenic
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Estrogen Antagonists
Triphenylethylene Derivatives Inverse Agonists
Chlorotrianisene (estrogenic)
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Selective Estrogen Receptor Modulators (SERM)
tissue specific activity . Estrogenic for bone
growth anti-estrogenic for uterine endometrial
growth
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Predict the Metabolism of Progesterone
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Typical Progesterone Agonists
Derivatize ring D
Derivatize rings A D
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Unusual Progesterone Agonists
Testosterone Derivatives
Ethisterone
Dimethisterone
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Progesterone Antagonist
Mifepristone
Onapristone
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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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Adrenocorticoids
Hydrocortisone (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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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
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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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Biochemical Mechanism of Action
Cortisol Aldosterone
Anti-inflammatory Action
Mineralocorticoid Action
Receptor Receptor
Lipocortin Aldosterone-
induced protein
Regulates Na-K-ATPase Pump
Na Influx
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Metabolism of Adrenocorticoids
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Structure-Activity Relationships
Anti- Salt-
Plasma inflammatory retaining
half activity activity life

Hydrocortisone 1 1
120 m
Cortisone 0.8
0.8 30 m
Prednisone 4
1 60 m
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Structure-Activity Relationships
Anti- Salt-
Plasma inflammatory retaining
half activity activity
life
Prednisone 4
1 60 m
Prednisolone 4 0.6
115-212 m
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Structure-Activity Relationships
Anti- Salt-
Plasma inflammatory retaining
half activity activity
life
Prednisolone 4
0.6 115-212 m
6a-methyl 4 0
78-188 m prednisolone
Triamcinolone 5
0 200 m
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Structure-Activity Relationships
Anti- Salt-
Plasma inflammatory retaining
half activity activity
life
Dexamethasone 30 0
110-210 m
Betamethasone 35 0
300 m
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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