Hormone Med Chem

Question 1

Natural Estrogen Structure

Answer 1

• C18 structures
• Aromatic A ring, no CH3 at C19
• Oxygen substituent at C3 and C17

Question 2

Estradiol Structure/Comments

Answer 2

• Most potent
• hydroxy at C3 and C17
• Main estrogen in postmenopausal, poor oral bioavailability
• More effective as a patch
• Can also be IM and vaginal cream

Question 3

Estriol Structure

Answer 3

• Partial agonist

- hydroxy at C3, C16, and C17

Question 4

Estrone Structure

Answer 4

• Inactive
• C17 = ketone
• Natural estrogen: main ingredient of conjugated estrogens

Question 5

Essential Features

Answer 5

• Molecules distance: 10.3-12.1 A between hydroxys

- Related to hydrogen bonds to estrogen receptors

Question 6

Estrogen Metabolism

Answer 6

• All estrogens interconvertible by estradiol dehydrogenases
• Mainly metabolized by the liver and yield same byproducts
• Estradiol = most potent, but least effective orally since it is broken down by 1 pass and hepatic metabolism (patch for better results

Question 7

Overcoming Estrogen Inactivation

Answer 7

• Stabilize C17 -OH
• Make esters at C3
• *Makes estrogen agonists**

Question 8

Types of Estrogen Agonists

Answer 8

• Steroidal estrogen
• Nonsteroidal estrogen
• Xenoestrogen/Phytoestrogens (environmental or from legumes)

Question 9

Steroidal Estrogens

Answer 9

• 17B OH (ethinyl/ethynyl on same carbon to protect it)
• 3 OH (turned into ester or sulfate conjugate prodrug)
• *Both of these increases its duration**

Question 10

17alpha Ethinyl

Answer 10

• Decreases conversion to estrone (oxidative metabolism)
• Blocks 17B hydroxysteroid dehydrogenase
• Increases oral bioavailability by 15-20x

Question 11

Ester Derivatives

Answer 11

• Administered IM
• Long estrogen effects over weeks
• Slowly hydrolyzed in vivo and at injection site

Question 12

Conjugated Estrogens

Answer 12

-Treat postmenopausal symptoms
Mixture of:
-Na+ salt of estrone sulfates
-Equilin - additional double bod on B ring
-17-alpha-dihydroequilin (reducing of 17-ketone group)

Question 13

Ethinyl-estradiol Comments

Answer 13

• Semi synthetic

- Oral Contraception

Question 14

SERM

Answer 14

• Used in hormone replacement therapy
• Agonist in bone
• Antagonist in breast/endometrium

Question 15

SERM Applications

Answer 15

• Treat estrogen-dependent breast cancer (Tamoxifen, Toremifen)
• Bone loss in postmenopause: Raloxoifene, Bazedoxifene
• Treat dyspareunia in postmenopause: Ospenifen (vaginal epithelium)

Question 16

Antiestrogens

Answer 16

• Triphenylethylene
• Cis: estrogenic (partial agonist)
• Trans: antiestrogenic
• Tamoxifen/Raloxifene: rigid, pure, without geometric isomer problems
• Prodrug whose metabolites do all the work (38-100x more affinity for receptor)

Question 17

Progestins

Answer 17

• Progesterone
• Rarely used therapeutically (poor oral bioavailability)
• Use progesterone agonists
• Use with estrogens for hormone replacement and as birth control

Question 18

Two Progesterone Classes

Answer 18

1. Progesterone agonists

2. Norethinedrone

Question 19

Progesterone Agonists

Answer 19

• 21C backbone
• Highly selective
• Hormone replacement
• Derivatize rings B & D

Question 20

Norethindone

Answer 20

• 19-nor
• Derived by 19-nortestosterone
• Oral contraceptives
• Potent progesterone activity and may have androgenic/other effects too
• Has 17-alpha ethinyl to increase progesterone activity

Question 21

2nd/3rd Generation Combinations

Answer 21

• More potent than estrones and decrease androgen activity
• Replace 18-methyl with an ethyl group
• EX: levonorgestrel, norgestimate

Question 22

Treatments of Menopause

Answer 22

Estrogens
• 17β-Estradiol
• Conjugated estrogens
• Esterified estrogens
• Estropipate

Progestins
• Medroxyprogesterone acetate
• Micronized progesterone

Selective estrogen receptor modulators (SERMs)
• Bazedoxifene
• Ospemifene