Steroids

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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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Examples of Steroid-based Drugs in Use Today
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Structures of Steroids
Structure and Nomenclature of the Steroid Nucleus
18
12
11
19
13
1
14
2
10
3
5
4
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Structures of Steroids
Structure and Nomenclature of the Steroid
Side-chain
21
22
20
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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
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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Biosynthesis and Metabolism of Cholesterol
HMG CoA reductase
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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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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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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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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

• 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

trans-trans-trans
cis-trans-trans
cis-trans-cis
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Anti-hyperlipidemic Drugs - Statins
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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
Bioavailabilty 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
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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Androgens Antagonists
Danazol (endometriosis)
Finesteride (baldness)
Bicalutamide (prostate cancer)
Flutamide (prostate cancer)
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Estrogenic Steroids
Overall Organization of the Topic

• Structure and nomenclature of natural estrogens
• - Estradiol, estrone, and estriol
• Biosynthesis and metabolism of estradiol
• Synthetic estrogens
• - Schulers hypothesis
• Estrogen antagonists
• - clomiphene and tamoxifen

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Estrogenic Steroids
Structure and Nomenclature of Natural Estrogens
Estradioll 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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Biosynthesis and Metabolism of Estradiol
cholesterol
pregnenolone testosterone
estriol
estrone estradiol
conjugation to glucuronides, sulfates, etc.
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Synthetic Estrogenic
ethinyl-estradiol
diethylstilbestrol
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
chlorotrianisene
clomiphene (estrogenic)

(anti-estrogenic)
tamoxifen (anti-estrogenic)
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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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Progestins
Progesterone
Progest-4-ene-3,20-dione
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Functions of Progesterone

• Maintains pregnancy
• Inhibits follicular maturation and ovulation
• prevents spontaneous uterine contraction

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Progesterone Metabolism
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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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Progesterone Agonists
2. Derivatization of A/B rings
Megestrol acetate
Medroxyprogesterone acetate (Oral Activity
12-25)
Chlomadinone acetate
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Progesterone Agonists
3. Testosterone Derivatives
Ethisterone
Dimethisterone
Relative Oral Activity 1
Relative Oral Activity 12
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Progesterone Agonists
4. 19-Nortestosterone Derivatives
Norethindrone
Norgestrel
Relative Oral Activity 5-10
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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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Hormone Replacement Therapy

• Osteoporosis
• Hot Flashes
• Heart Diseases
• Cancer

Link to Latest on HRT
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Progesterone Antagonist
RU-486 Mifepristone
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Adrenocorticoids
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Adrenocorticoids
Aldosterone (11b,21-dihydroxy- pregn-4-ene-3,18,20
-trione)
Hydrocortisol (11b,17a,21-trihydroxy- pregn-4-ene-
3,20-dione)
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Adrenocorticoids

• Addisons Disease
• Cushings Disease
• Conns Syndrome

? Disease States
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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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Overall Equilibrium in Aldosterone
Opened form hemi-acetal
form
Aldosterone
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Overall Structure of Adrenocorticoids
planar A ring
Differences in the substitution pattern
3D structure of hydrocortisol
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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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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
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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
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