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Drug Action II > Block 5: Estrogen, Progestin, Androgens Med Chem > Flashcards

Block 5: Estrogen, Progestin, Androgens Med Chem Flashcards

1
Q

What are the sex hormones?

A

Estrogens
Progestins
Androgens

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2
Q

T/F: Sex hormones are sex-specific?

A

False: All of the sex hormones are found in both males and females, but in differing proportions.

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3
Q

Describe the stucture of Estrogens?

A

C18 steroids that have an unsaturated A ring (aromatic)

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4
Q

What is the the most potent estrogen?

A

Estradiol

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5
Q

Describe the structure of preogestins?

A

C21 steroids that maintain a 3-keto-4,5-ene functionality (ene-one) similar to the adrenocorticoids

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6
Q

What is the most potent progestin?

A

Progesterone

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7
Q

Describe the structure of androgens?

A

C19 steroids with oxygens (hydroxyl or ketone) in both the 3- and 17-positions

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8
Q

What is the most common naturally occurring androgens in the blood?

A

Testosterone

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9
Q

What is a more potent form of testosterone?

A

5α-dihydrotestosterone

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10
Q

What is the first estrogen crystallized from urine?

A

Estrone

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11
Q

What are the 3 classic estrogens?

A
  1. Estrone
  2. 17β-estradiol
  3. Estriol
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12
Q

Where is estrogen biosynthesized in women?

A

Ovaries from cholesterol

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13
Q

Where is estrogen biosynthesized in men?

A

testes

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14
Q

What synthesizes estrogen in both women and men?

A

Adrenal cortex, hypothalamus, adenohypophysis

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15
Q

What enzymes are required for ene-one activation?

A
  1. 5-ene-3β-hydroxysteroid dehydrogenase
  2. 3-oxosteroid-4,5-isomerase
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16
Q

What is the critical step in the conversion of androgen to estrogens?

A

Aromatization

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17
Q

What is the preferred substrate of aromatase?

A

Androstenedione (testosterone is also a substrate)

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18
Q

Sx of aromatase deficiency?

A

Failure of females to develop secondary sexual characterisitcs at puberty and failure to become sexually mature

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19
Q

What is required to convert androstenedione to estrone?

A

3 step reaction of 3 molecules of O2 and NADPH catalyzed by CYP19

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20
Q

What are the components of a CYP enzyme?

A

Heme prostetic group that carried by histidine residues and grabs to molecular oxygen

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20
Q

How is estrogen metabolized?

A
  1. Hydroxylation at both orhto-positions to the 3-phenolic hydroxy by estrogen 2/4-hydroxylase producing a catechol
  2. The catechol estrogens are unstable in vivo and are rapidly metabolized to their O-methoxy metabolites by COMT and get conjugated
  3. The catechol estrogens can bind to estrogen receptors and produce a weak estrogenic effect (slightly active with short half-life)
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21
Q

What are the ezymes that inteconvert the 3 classic estrogen molecules?

A

Estradiol dehydrogenase: Estradiol and estrone (interconvertable)
16α-hydroxylase: estradiol to estriol and estrone to 16α-Hydroxyestrone (non-interconvertible)

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22
Q

What is estradiol potent?

A
  1. high affinity for the estrogen receptor
  2. Very low oral bioavailability due to oxidative metabolism and conjugation
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23
Q

What does estradiol bind to?

A

sex hormone-binding globulin (SHBG)

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24
Q

What is the primary metabolite of estradiol metabolism?

A

2-hydroxyestradiol: excreted as either the sulfate or glucuronide metabolite

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25
Q

What is the therapeutic use for estradiol?

A

An abdominal patch for treatmening menopausal symptoms

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26
Q

What is the purpose of having an Ethinyl Estradiol?

A

Block the rapid oxidative metabolism of estradiol after oral administration, attempts were made to block the 17β-hydroxyl moiety

A 17α-ethinyl substituent proved to be the most effective and resulted in ethinyl estradiol

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27
Q

What is Mestranol?

A

3-O-methyl prodrug derivative of ethinyl estradiol

28
Q

What are the common estradiol esters?

A

17β-valerate and 17β-cypionate

29
Q

When are esters on estradiol preferred?

A

When long-term estrogenic therapy is needed, 17β-esters are typically preferred

30
Q

Describe the SAR of estrogen?

A
  1. Substitutions at C1 greatly reduce activity: C2 and C4 can accommodate small substitutions
  2. Removal of either oxygen at C3 or C17 diminishes activity: Epimerization of the C17 hydroxyl to 17α-hydroxyl also diminishes activity
  3. Enlargement of the D-ring to a 6-membered ring diminishes activity

17a-alkyl substituents: Oral bioavailabity, no oxidation

31
Q

What are conjugated estrogens?

A

Water-soluble metabolites of naturally occurring estrogens are also utilized as estrogenic therapies

Urine of pregnant maters marketed as Estrogens USP

32
Q

What is in a estrogens USP?

A

Mixture of sodium sulfate esters (3-O-esters) of estradiol metabolites: primarily estrone and equilin

Mares produce 2 unique estrogens not found in humans

33
Q

What is estropipate?

A

Orally available sulfate conjugate (piperazine estrone sulfate)

34
Q

What are examples of nonsteroidal estrogens?

A
  1. Stilbene found in plants
  2. Diethylstilbestrol (DES): cheaper and of medicinal importance for prostate cancer
    * Can cause neoplasia and uterine cancer
    * Trans isomer of all stilbene derivatives is the more potent isomer
  3. Hexestrol
  4. Dienestrol
35
Q

What is the clinical use for estrogen antagonists?

A
  1. Modify reproductive processes
  2. Estrogen-sensitive breast cancer
36
Q

What are the types of estrogen antagonists?

A
  1. Impeded estrogens
  2. Triphenylethylene antiestrogens
  3. Aromatase inhibitors
37
Q

Describe the structure of Triphenylethylene?

A

Antiestrogen from MER25, a weak antiestrogen

Very strong and provides persistent binding to the estrogen receptor

38
Q

What is climiphene? Indication?

A

Clomiphene citrate (Clomid): estrogenic and antiestrogenic properties (partial agonist)

Indication: Induce ovulation for infertility

39
Q

What are the isomers of climiphene?

A

It is dosed as the racemic mixture
Z isomer: estrogenic activity
E isomeer: antiestrogenic activity

40
Q

MOA of clomiphene? Absorption? Metabolized? Excretion?

A

MOA: binds to estrogen receptors in the hypothalamus, leading to a blockade of the feedback inhibition exhibited by estrogens (increasing secretion of FSH and LH)
Absorption: Absorbed from the GIT after PO admin with a half-life of 5 days
Metabolized: Liver
Excreted: Feces

41
Q

What is tamoxifen? Indication?

A

Estrogen agonist-antagonist (partial agonist) used for estrogen dependent breast cancer

Also classified as a an antineoplastic agent or as a selective estrogen receptor modulator (SERM)

42
Q

What is the isomer of tamoxifen?

A

PO Z-isomer metabolized by rapid dethylation from CYP3A4

43
Q

What is the first SERM to be marketed?

A

Raloxifene (Evista): benzothiophene derivative

44
Q

How is raloxifene metabolized?

A

Rapid and extensive first-pass metabolism to its eventual glucuronide conjugates

45
Q

What is toremifene? How is it metabolized?

A

Related to tamoxifen but contains a chlroine on the ethyl side-chain
Metabolism: Undergoes rapid demethylation to the primary metabolite, N-demethyltoremifene (CYP3A4)

46
Q

MOA of aromatase? Indication?

A

Competitive inhibitors of aromatase that selectively inhibit the conversion of testosterone to estrogens in all tissues
MOA: Binding of the N-4 nitrogen of the azole with the heme iron atom of the CYP19 complex
Indication: Treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy

Anastrozole and letrozole

47
Q

What are progestins?

A

C21 steroidal hormones most notably involved with the female menstrual cycle, pregnancy, and embryogenesis

48
Q

What is the most common pregnanes?

A

5β-pregnanediol

49
Q

What does biosythensis of progestin occur?

A

Luteal phase of of the reproductive cycle

50
Q

How is progesterone metabolized?

A

Primarily excreted as the conjugated 5β-pregnanediol and rapidly metabolized in the liver

51
Q

What is the function of synthetic progestin?

A

Progesterone has poor bioavailability therefore has become a natural target for development through structural modification

Known as pregnanes or norandrostans

52
Q

What is the difference between pregnanes and norandrostanes?

A

Pregnanes: progesterone and derivatives
Norandrostanes: testosterone derivatives

53
Q

What is the first PO biavailable progesterone derivate?

A

17α-acetoxyprogesterone however it is not extensively used

54
Q

How did they adapt 17α-acetoxyprogesterone have enhanced bioavailability?

A

Medroxyprogesterone contains a 6a-methyl substituent that has very little estrogenic activity and no androgenic activity

Prevents metabolic hydroxylation

55
Q

How does megestrol differ from medroxyprogesterone?

A

Enhanced progestestational activity with 6-substituted-17α-acetoxyprogesterones when a double bond is introduced at positions 6 and 7 creating megestrol acetate and chlormadinone acetate

56
Q

Indication of Megestrol?

A

Breast and endometrial carcinoma

57
Q

What is the first synthetic progestin that has been used clinically?

A

ethisterone

58
Q

What makes Ethisterone effective?

A

Enhanced progestational activity is attributed to the introduction of methyl groups at the 6α-position and C-21 position:
1. No 17-acetyl group
2. Revealed that the C-19 methyl group was unnecessary for activity

The 19-nor analogues proved have activity equal to or greater than parenterally administered progesterone

59
Q

What are the potent PO active progestins?

A

Norethindrone, norethynodrel, ethynodiol diacetate

60
Q

What is the most common use for norethindrone?

A

Often combined with estrogen (ethinyl estradiol or mestranol) as an oral contraceptive

61
Q

How is norethindrone metabolized?

A

completely and rapidly deacetylated after oral administration

62
Q

How are most oral contraceptive steroids broken down in the body?

A

Absorbed and extensively metabolized in either the GI mucosa or by first-pass effect

63
Q

How is desogestrel metabolized?

A

To 3-ketodesogestrel (etonogestrel), which is active and used in combination with ethinyl estradiol in the NuvaRing

64
Q

Describe the SAR of progestin?

A
  1. The activity of 17α-hydroxyprogesterones can be enhanced through the addition of a 6-7 double bond (Substitution of a halogen at the 6-position is also effective)
  2. Substitution of a chlorine at C21 prevents metabolic hydroxylation and enhances oral activity.
65
Q

MOA of progestin antagonist? Examples?

A
  1. Antagonize the activity of progesterone by competing for receptor binding of the progesterone receptor
  2. By blocking progesterone activity, mifepristone can block the implantation of fertilized eggs and interrupt early stages of implantation

Mifepristone, the well-known RU-486

66
Q

Describe the biosynthesis and metabolism of progestin?

A
67
Q

What modifications were made to decrease metabolism of synthetic androgens?

A
  1. Blocking the metabolism of the 17β-hydroxyl can be accomplished by addition of a 17α-substituent
  2. produced 17α-methyltestosterone
  3. Most common substituent has a methyl

Incorporation of a 9α-fluoro substituent to the active 17α-methyltestosterone increased activity
* Produced Fluoxymesterone, which has 20x the anabolic activity and 10x the androgenic activity
* ADR: unwanted sodium and water retention by mimicking spiranolactone

68
Q

Describe the modification of anabolic steroids?

A
  1. The removal of the C19 methyl group from the androgenic steroid nucleus results in the 19-norandrogens
  2. Substitution of a 17α-ethyl group such as in norethandrolone or ethylestrenol provides very potent agents with an increased ratio of anabolic to androgenic activity
  3. Insertion of an oxygen into either the A or D ring produces active agents, but with decreased potency over many of the other agents

Drug Action II (28 decks)

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