Test 1 Med Chem for Adrenocorticoids & Sex Hormones Flashcards

Question

Testosterone Derivatives

Answer 1

* Testosterone cypionate * Testosterone enanthate * 17a- Methyltestosterone * Fluoxymesterone (Androxy)

Answer 2

* 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)

Answer 3

* 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

Answer 4

* 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**

Answer 5

* 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)

Answer 6

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

Answer 7

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

Answer 8

* 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.

Answer 9

* 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)

Answer 10

* Casodex * Androgen Antagonist * t_1/2= approx 6 days

Answer 11

* Apo-Flutamide * Androgen Antagonist * Metabolism * Major: 2-hydroxyflutamide (more potent) * hydrolysis * 2-Hydroxyflutamide (t_1/2: ~5-6 hrs)

Answer 12

* Nilandron * Androgen Antagonist * t _1/2 : ~ 50 hours

Answer 13

* Estradiol * ethinyl estradiol * esters of estradiol * conjugated Estrogens

Answer 14

* Estradiol * Estrone * Estriol

Answer 15

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

Answer 16

* 60 to 80% of the circulating estrogen * 10-fold less potent than estradiol

Answer 17

* Very weak estrogen * 10 to 20% of the circulating estrogen

Answer 18

* When administered orally, estradiol is conjugated and oxidatively metabolized resulting in its low oral bioavailability

Answer 19

* Ethynyl estradiol (EE) * Mestranol

Answer 20

* 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

Answer 21

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

Answer 22

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

Answer 23

* 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

Answer 24

* 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

Answer 25

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

Answer 26

* **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)

Answer 27

* 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)

Answer 28

* 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)

Answer 29

* 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)

Answer 30

* 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**

Answer 31

* 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

Answer 32

* 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

Answer 33

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

Answer 34

* 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

Answer 35

* 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

Answer 36

* 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

Answer 37

c. Dutasteride (5a-reductase inhibitor)

Answer 38

* 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)

Answer 39

* 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**

Answer 40

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

Answer 41

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

Answer 42

* 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

Answer 43

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

Answer 44

* 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

Answer 45

* 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

Answer 46

* 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

Answer 47

o Mifepristone (Mifeprex)

Answer 48

* 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**

Answer 49

Ulipristal acetate (ella, ellaOne)

Answer 50

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