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2016 Endocrine > Test 1 Med Chem for Adrenocorticoids & Sex Hormones > Flashcards

Test 1 Med Chem for Adrenocorticoids & Sex Hormones Flashcards

1
Q

Classes of steroidal hormones

A

2 classes:

  • Adrenocorticoids
    • Glucocorticoids
    • Mineralocorticoids
  • Gonadal Steroids
    • Androgens
    • Estrogens
    • Progestogens
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2
Q

Steroid Nomenclature and structure

A
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3
Q

Adrenocorticoid steroid production location

and types of adrenocorticoids

A
  • Adrenal glands: Located above the kidneys.
    • Medulla: Inner core; secretes catecholamines (epinephrine)
    • Cortex: Synthesizes steroid hormones (adrenocorticoids)
  • Adrenocorticoids
    • Glucocorticoids:
      • Regulate carbohydrate, lipid, and protein metabolism
    • Mineralocorticoids:
      • Influence salt balance and water retention
  • Many naturally occurring and semisynthetic analogues exhibit both glucocorticoid (GC) and mineralocorticoid (MC) action
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4
Q

Adrenocorticoid biosynthesis pathway

A
  • Cholesterol is the precursor molecule
    • Cholesterol→pregnenolone
    • Pregnenolone can take 2 paths
      • Pregnenolone→progesterone→intermediates→aldosterone
      • Pregnenolone→intermediates→hydrocortisone
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5
Q

Adrenocorticoids: General SAR

Hydrocortisone vs Aldosterone

A
  • Similarities:
    • Carbonyl group @ C3
    • Double bond (C4 and C5)
    • -OH @ C11
    • Hydroxymethylketone (-CO-CH2-OH) on C17
  • Differences:
    • Hydrocortisone has 17-a OH
    • Aldosterone has an aldehyde FG at C13
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6
Q

List of Adrenocorticoids

A

Hydrocortisone (glucocorticoid with mineralo-properties)

Fludrocortisone (used as mineralocorticoid)

Prednisolone (glucocorticoid)

Triamcinolone (glucocorticoid)

Dexmethasone (glucocorticoid)

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7
Q

Hydrocortisone Esters

A

Different formulations: useful for different routes of administration/sites of action

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8
Q

Hydrocortisone

A
  • R=H
    • Well absorbed orally.
    • Bioavailability: 95%;
    • Biologic t½ 8 to 12 hours
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9
Q

Hydrocortisone acetate

A
  • R=Acetate
    • Systemic absorption from intra-articular injection sites in 24 to 48 hours
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10
Q

Hydrocortisone cypionate

A
  • R=Cypionate
  • Used orally for slower absorption from the GIT
    • contains a lipophilic side chain→ slows absorption
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11
Q

Hydrocortisone sodium phosphate

A
  • R=sodium phosphate
    • Hydrolyzed by phosphatases
    • t1/2 < 5 minutes
    • IV or IM. (highly ionic molecule → rapid solubility)
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12
Q

Hydrocortisone butyrate and valerate

A
  • R=butyrate or vlerate
    • used topically
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13
Q

Hydrocortisone Metabolism

A
  • 11 ß-hydroxysteroid dehydrogenase (oxidation)→inactive cortisone
  • 5 ß-reductase (reduction)→inactive 5 ß-dihydrocortisol→3à- hydroxysteroid dehydrogenase→inactive urocortisol
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14
Q

Fludrocortisone

A
  • 9à-fluoro hydrocortisone analogue
  • A potent corticosteroid (compared to hydrocortisone)
  • Widely used as mineralocorticoid (more mineralocorticoid properties than hydrocortisone due to Fluoro group)
  • Promotes increased reabsorption of sodium and loss of potassium from renal distal tubules
  • Biologic t½: 18-36 hrs (Increased half-life compared to hydrocortisone)
  • DOA: 1-2 days
  • Use: Adrenocortical insufficiency in Addison’s disease
  • Not classified as a glucocorticoid, even though it has properties – may lead to edema
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15
Q

Prednisolone

A
  • Double bond @ 1 and 2
    • ↑ GC activity
    • Does not have significant MC activity
  • Biologic t½: 18-36 hrs
  • Ester forms: acetate, tert-butyl acetate, sodium phosphate
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16
Q

Prednisolone Metabolism

A
  • Major metabolites utilize CYP450: 6ß- and 16à-hydroxy are primarily excreted as active glucuronide conjugates (several hydroxy groups) in the urine
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17
Q

Triamcinolone

A
  • glucocorticoid
  • Low BA: 23%
  • Does not have significant MC activity
  • Biologic t½: 18-36 hrs
  • DOA: 1.0-1.5 days
  • Esters: Administered IM or intraarticularly for a prolonged release
  • Triamcinolone diacetate has a DOA from 1 to 8 weeks
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18
Q

Dexmethasone

A
  • 16a-methyl group
    • Increases the anti-inflammatory activity by increasing lipophilicity and receptor affinity. About 5 x as active as prednisolone
  • Biologic t½: 36-54 hrs
  • DOA: ~ 3 days
  • What is Betamethasone? (Perhaps it is slightly more active than dexamethasone) – contains a beta-methyl group @ 16 position
    • Hydroxy group is replaced with methyl group à more lipophilic (better receptor activity)
    • Potency: Dexamethasone >> prednisone >> hydrocortisone
    • DOA: Dexamethasone >> prednisone >> hydrocortisone
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19
Q

Adrenocorticoid Antagonists

A
  • Agents that compete for binding to steroid receptors
    • Antimineralocorticoid/ MC receptor antagonist
      • Spironolactone (Aldactone)
    • Antiglucocorticoid/ GC receptor antagonist
      • Mifepristone (Mifeprex)
        • Mifepristone is also a progestin antagonist
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20
Q

Spironolactone

A
  • Structural features: 3-keto-4-ene A ring; 7α-substituent; lactone ring
  • Uses:
    • Edema from hyperaldosteronism
    • Potassium-sparing diuretic; Increased Na+ excretion and K+ retention
  • Absorption: Oral: 90 %
  • t ½ elimination: Spironolactone: 78-84 minutes; Canrenone: 10-23 hours
  • Metabolism: Canrenone (active)
  • Does spironolactone bind to other receptors? Yes – binds to steroid receptors
  • Adverse effects: Hyperkalemia, Sexual side effects (gynecomastia), Tumorigenic [US Boxed Warning]
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21
Q

Metyrapone

A
  • MOA:
    • Inhibits 11b-hydroxylase (stop making hydrocortisone)
    • Interfering with cortisol biosynthesis
  • Uses:
    • To test hypothalamic-pituitary ACTH function
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22
Q

Sex Hormones

A
  • Androgens
    • E.g. Testosterone
  • Estrogens
    • Steroidal
      • E.g., Conjugated; Esterified
    • Non-steroidal
      • E.g., Stilbenes; Phytoestrogens
  • Progestogens
    • E.g. Progesterone
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23
Q

Biosynthesis of Sex Hormones

A

Shift of double bond = isomerase reaction

Estrogens are the only steroids that have an aromatic “A” ring (some exceptions)

How does progesterone differs from testosterone: progesterone has carbonyl @ C17, while testosterone has a hydroxy group

Focus on: aromatase, 5a-reductase

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24
Q

Testosterone→5a-Dihydrotestosterone

A
  • For androgen replacement therapy
  • Have both androgenic and anabolic activities
    • Why do you want to block the synthesis of 5a-reductase?
      • Used in prostate cancer and BPH
    • How can you reduce the effects of this molecule (naturally occurring)?
      • Block the receptor – give anti-androgens
    • Can undergo oxidation→ketone (tertiary alcohols are not oxidizable)
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25
Q

Testosterone Derivatives

A
  • Testosterone cypionate
  • Testosterone enanthate
  • 17a- Methyltestosterone
  • Fluoxymesterone (Androxy)
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26
Q

Testosterone Cypionate and Enanthate

A
  • Testosterone Derivatives
    • Testosterone esters (17-β esters)
      • testosterone enanthate and cypionate are lipophilic
        • Add lipophilic side chains to prolong the DOA
      • I.M.: Cypionate and enanthate esters
      • DOA: ≤2-4 weeks
      • Metabolism:
        • To DHT via 5a-reductase
        • To estradiol (aromatase)
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27
Q

17a- Methyltestosterone

A
  • Testosterone Derivative
    • Increased oral bioavailability (due to addition of methyl group)
    • 17a alkyl group
      • Reduces susceptibility to oxidative metabolism
    • Has the androgenic and anabolic activities of testosterone
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28
Q

Fluoxymesterone

A
  • Testosterone Derivative
    • Aka Androxy
    • 9α-fluoro group
      • ↑ activity
      • 20 times anabolic activity of 17a-methyltestosterone
      • 10 times the androgenic activity of 17a-methyltestosteone
    • t1/2 elimination: 10-100 minutes
    • Adverse effect: Sodium and water retention that could lead to edema
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29
Q

5a-reductase Inhibitors

A
  • MOA: Mechanism-based inhibitors (binds permanently)
    • Irreversible modification of 5α-reductase.
    • Natural substrate of 5a-reductase is testosterone – these molecules contain alpha, beta unsaturated amide
  • Uses: benign prostatic hyperplasia
    • Finasteride (Proscar)
    • Dutasteride (Avodart)
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30
Q

Finasteride

A
  • Proscar
  • 5a-reductase inhibitor
    • Reduces DHT levels:
      • ~ 70% plasma
      • ~ 85 to 90% in prostate
    • Elimination t1/2 (hours) :
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31
Q

Dutasteride

A
  • Avodart
  • 5a-reductase Inhibitor
    • Greater and consistent reduction of plasma DHT levels
    • Elimination t1/2 : 5 weeks
    • Higher lipophilicity (due to the aromatic ring)
32
Q

5a-reductase inhibtor SAR

A
  • 5a-reductase needs NADPH so
    • 5a-reductase inhibitors need the double bond between 1 and 2
    • the ketone at 3, a
    • nd the N-H at 4 to be functional.
33
Q

Androgen Antagonists

A
  • Treatment for prostate cancer
  • Goal of antiandrogen therapy:
    • Block the effects of testosterone and DHT on ARs (androgen receptors)
  • MOA: block the binding of androgens to androgen receptors
  • All have Amides
    • Bicalutamide (Casodex)
    • Flutamide (Apo-Flutamide)
    • Nilutamide (Nilandron)
34
Q

Bicalutamide

A
  • Casodex
  • Androgen Antagonist
    • t1/2 = approx 6 days
35
Q

Flutamide

A
  • Apo-Flutamide
  • Androgen Antagonist
  • Metabolism
    • Major: 2-hydroxyflutamide (more potent)
    • hydrolysis
  • 2-Hydroxyflutamide (t1/2: ~5-6 hrs)
36
Q

Nilutamide

A
  • Nilandron
  • Androgen Antagonist
    • t 1/2 : ~ 50 hours
37
Q

Steroidal Estrogens

A
  • Estradiol
  • ethinyl estradiol
  • esters of estradiol
  • conjugated Estrogens
38
Q

Estradiols

A
  • Estradiol
  • Estrone
  • Estriol
39
Q

Estradiol

A
  • Most potent endogenous estrogen
  • High affinity for Estrogen Receptor
  • 10 to 20% of the circulating estrogen
  • Oral Administration: Low oral bioavailability
40
Q

Estrone

A
  • 60 to 80% of the circulating estrogen
  • 10-fold less potent than estradiol
41
Q

Estriol

A
  • Very weak estrogen
  • 10 to 20% of the circulating estrogen
42
Q

Estrogen Metabolism:Interconversion

A
43
Q

Estrogen Metabolism of Oral Admin

A
  • When administered orally, estradiol is conjugated and oxidatively metabolized resulting in its low oral bioavailability
44
Q

Ethinyl Estradiols

A
  • Ethynyl estradiol (EE)
  • Mestranol
45
Q

Ethynyl estradiol

A
  • EE
    • Ethinyl estradiol
  • A synthetic analogue
  • More potent than estradiol
  • Oral bioavailability: ~ 40%
  • t 1/2: 26 hours
  • Alkyne group prevents metabolic oxidation –OH group @ C17
  • Undergoes first-pass metabolism (How?)
    • Gives rise to glucuronide or sulfate – can be cleaved by bacteria (decreased estrogen effect when given with antibiotics) à readily excreted
46
Q

Mestranol

A
  • Ethinyl estradiol
  • A prodrug
    • Metabolized to EE via O-demethylation
  • Alkyne group prevents metabolic oxidation –OH group @ C17
47
Q

Esters of Estradiol

A
  • Estradiol 17β-valerate
  • Estradiol cypionate
    • Longer DOA ester prodrugs
    • Usually are administered IM (Depot)
    • When adding an ester group, the molecule has increased lipophilicity
48
Q

Estradiol 17β-valerate

A
  • Ester of Estradiol
    • Longer DOA ester prodrug
    • Usually are administered IM (Depot)
    • When adding an ester group, the molecule has increased lipophilicity
  • DOA of 14 to 21 days
49
Q

Estradiol cypionate

A
  • 17β-cyclopentyl propionate
  • Esters of Estradiol
    • Longer DOA ester prodrugs
    • Usually are administered IM (Depot)
    • When adding an ester group, the molecule has increased lipophilicity
  • DOA of 14-28 days
50
Q

Conjugated Estrogens

A
  • Estrone Sulfate
  • Equiline Sulfate
  • Mixture (several conjugated estrogens)
  • Initially from urine of pregnant mares
  • Sulfate groups must be hydrolyzed to afford active estrogens
51
Q

Nonsteroidal Estrogens

A
  • Steroid nucleus is not required for estrogenic action
    • Does not contain the steroid template, but still has estrogenic properties
  • DES was correlated with abnormal growth in the offspring
  • No longer used
  • Include
    • Diethylstilbestrol (DES)
    • Estradiol (Diethylstilbestrol)
52
Q

Agents that interfere with estrogen activation of receptor

A
  • Selective estrogen receptor modulators (SERMs)
    • Drugs: Tamoxifen (Soltamox), Toremifene (Fareston), Raloxifene (Evista), Ospemifene (Osphena), Bazedoxifene
    • Mixed estrogen agonists
    • Partial agonists or antagonists in some tissues
    • Agonist effects in other tissues
  • Pure Estrogen Receptor Antagonists
    • Drug: Fulvestrant (Faslodex)
53
Q

Tamoxifen

A
  • not a steroid
  • SERM
  • Uses: Metastatic breast cancer (estrogen dependent)
    • Antagonist: breast
    • Agonist: uterus
  • Pharmacokinetics:
    • Absorption: Well absorbed: Excellent BA
    • Distribution: High in uterus and breast
    • Protein binding: 99%
    • t ½: 5 to 7 days
    • Adverse effects: Increase the risk of uterine cancer and thromboembolic events (acts as an agonist in uterine cells)
54
Q

Tamoxifen Metabolism

A
  • Metabolism: Endoxifen and 4-hydroxy-tamoxifen are more potent than Tamoxifen
  • CYP2D6 inhibitors (e.g., paroxetine, fluoxetine) decrease the effectiveness of Tamoxifen (the metabolites are more active than the parent drug)
55
Q

Toremifene

A
  • Fareston
  • SERM
  • Very similar to tamoxifen, but metabolism differs, has CL group
    • Uses: Metastatic breast cancer in postmenopausal women
      • Antagonist: breast
      • Agonist: uterus
    • Absorption: Well absorbed
    • Half-life elimination: ~5 days
    • CYP 3A4 is the major metabolizing enzyme
56
Q

Raloxifene

A
  • Evista
  • SERM
  • Tissue specific activities
    • agonist in bone: strengthens bone formation; reduces resorption
    • antagonist in breast and uterus
  • Unique carbonyl hinge in Raloxifene makes it selective for ER in bones
  • Used in osteoporosis.
    • Risk reduction for invasive breast cancer in postmenopausal women with osteoporosis
57
Q

Fluvestrant

A
  • Faslodex
  • Pure Estrogen Recptor Antagonist
    • Acts as an antagonist at all receptors
  • An aliphatic fluoro derivative of estradiol
  • Long aliphatic chain (7a) induces structural changes in ER rendering it inactive
  • Uses: Hormone receptor positive metastatic breast cancer in postmenopausal women
  • Oral bioavailability poor (due to long lipophilic tail) – wont solubilize
  • Administration: IM
  • t ½: 40 days (released from the muscle – depot activity)
  • Metabolites: Less active or have similar activity to fulvestrant
58
Q

Agents that limit Estrogen Biosynthesis

A
  • Aromatase Inhibitors: Block the conversion of androgens to estrogens
    • Triazole Derivatives:
      • Anastrozole (Arimidex), Letrozole (Femara)
    • Steroidal Agent
      • Exemestane (Aromasin)
59
Q

Anastrozole

A
  • Arimidex
  • Triazole derivative :limits estrogen biosynthesis
    • Competitive inhibitors of aromatase (competing with testosterone) à decreased levels of estradiol in the body
    • N-4 nitrogen of the triazole ring interacts with the heme iron atom of aromatase enzyme complex.
  • Absorption: Well absorbed
  • Protein binding: 40%
  • t ½: ~ 50 hrs
  • Metabolism: N-dealkylation, hydroxylation, and glucuronidation
60
Q

Letrozole

A
  • Femara
  • Triazole Derivative: limits estrogen biosynthesis
  • Competitive inhibitors of aromatase (competing with testosterone)
    • decrease levels of estradiol in the body
  • N-4 nitrogen of the triazole ring interacts with the heme iron atom of aromatase enzyme complex.
  • Well absorbed
  • t ½: ~ 2 days
  • Metabolism: Inactive carbinol metabolite and others
61
Q

Exemestane

A
  • Aromasin
  • Steroid-based estrogen inhibitor
    • structure related to androstenedione
  • Binds irreversibly to aromatase; A suicide inhibitor
  • Absorption: ~42% following oral administration
  • Protein binding: 90%
  • t ½: 24 hrs
  • Metabolism: Extensive; oxidation of methylene group (=CH2), reduction of 17-keto group; formation of many metabolites; metabolites are inactive
62
Q
  1. Which of the following agents will block the enzyme that is responsible for converting testosterone to DHT?
    a. Anastrozole (aromatase inhibitor)
    b. Flutamide (anti-androgen)
    c. Dutasteride (5a-reductase inhibitor)
    d. Tamoxifen (SERM)
    e. Exemestane (aromatase inhibitor
A

c. Dutasteride (5a-reductase inhibitor)

63
Q

Progestins

A
  • Progestin Activity is restricted to a steroid nucleus
  • Natural Progestins
    • Progesterone
  • Progesterone derivative (synthetic)
    • Medroxyprogesterone acetate
    • Megesterol acetate
  • 19-nortestosterone derivative (synthetic)
    • Norethindrone (norethisterone)
    • Norgestrel (racemic)
    • Levonorgesterol (single isomer)
    • Desogestrel
  • Drospirenone (Micellaneous Progestin)
64
Q

Progesterone

A
  • Natural progestin
  • Metabolism: hydroxylation, reduction, inactive diol to glucuronide and sulfate conjugates
  • t1/2: 5 to 10 minutes (very short)
  • Low oral bioavailability (< 10%) – undergoes extensive metabolism
  • Other Routes: IM, Intravaginally
65
Q

Medroxyprogesterone acetate

A
  • Progesterone derivative (synthetic)
  • First-generation agent
  • High oral bioavailability
  • Deacetylated following oral administration.
  • Metabolism: Similar to those for progesterone, except for 6a-hydroxylation.
66
Q

Megesterol acetate

A
  • progesterone derivative (synthetic)
  • First-generation agent
  • C6-C7 double bond increases progestin activity
  • Orally: <10% dose is metabolized
67
Q

Norethindrone

A
  • norethisterone
  • 19-nortestosterone derivative (synthetic)
  • First-generation agent
  • No 19 CH3 group
  • Some androgenic activity, but has more progesterogenic properties (similar to testosterone structure)
  • No glucocorticoid or antimineralocorticoid activity
  • Acetylation of the 17β-OH of norethindrone increases the duration of action of the drug
68
Q

Norgestrel

A
  • racemic
  • 19-nortestosteerone derivative (synthetic)
  • Methyl group @ carbon 18 ↑ activity
  • Second generation→ more potent than the previous generation
69
Q

Levonorgesterol

A
  • single isomer
  • 19-nortestosteerone derivative (synthetic)
  • Methyl group @ carbon 18 ↑ activity
  • Second generation→ more potent than the previous generation
  • Levogestrel vs Norgestrel
    • Pharmacologically active
    • Some androgenic activity
    • No glucocorticoid or antimineralocorticoid action
70
Q

Desogestrel

A
  • 19-nortestosterone derivative
  • Third generation (better than previous generation in some aspects, not in others)
  • Prodrug
    • Metabolized to active Etonogestrel (3-ketodesogestrel)
  • Lower/ no androgenic activity than older synthetic progestins
  • Increase in the risk of venous thrombo-embolism
71
Q

Drospirenone

A
  • Micellaneous Progestin
  • Fourth generation
  • Progestin with antimineralocorticoid activity
  • Structurally similar to spironolactone
    • K -sparing diuretic effects similar to spironolactone
    • Can increases potassium levels
  • Cylcopropyl groups increase progestogen activity
  • A higher risk of thromboembolism
72
Q

Progestin Antagonists

A

o Mifepristone (Mifeprex)

73
Q

Mifepristone

A
  • Mifeprex
  • Progestin Antagonist (at low doses)
    • Termination of intrauterine pregnancy (through 49 days)
  • High doses exert antiGC activity by blocking the GC receptor
    • Treatment of hyperglycemia with Cushing’s syndrome
  • Rapidly absorbed. Oral bioavailability: ~ 70%
  • Mean t1/2 : 20 hrs. Protein binding: 98%
  • Metabolism: N-demethylation and hydroxylation of the 17-propynyl chain
74
Q

Progesterone Receptor Modulator

A

Ulipristal acetate (ella, ellaOne)

75
Q

Ulipristal acetate

A
  • ella, ellaOne
  • Progesterone-receptor modulators
  • A derivative of 19-norprogesterone
  • Selective progesterone receptor modulator
  • Emergency contraceptive
    • Inhibit ovulation
    • Anti-proliferative effects in the uterus

2016 Endocrine (19 decks)

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