Hormone Med Chem Flashcards
Natural Estrogen Structure
- C18 structures
- Aromatic A ring, no CH3 at C19
- Oxygen substituent at C3 and C17
Estradiol Structure/Comments
- 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
Estriol Structure
- Partial agonist
- hydroxy at C3, C16, and C17
Estrone Structure
- Inactive
- C17 = ketone
- Natural estrogen: main ingredient of conjugated estrogens
Essential Features
- Molecules distance: 10.3-12.1 A between hydroxys
- Related to hydrogen bonds to estrogen receptors
Estrogen Metabolism
- 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
Overcoming Estrogen Inactivation
- Stabilize C17 -OH
- Make esters at C3
- *Makes estrogen agonists**
Types of Estrogen Agonists
- Steroidal estrogen
- Nonsteroidal estrogen
- Xenoestrogen/Phytoestrogens (environmental or from legumes)
Steroidal Estrogens
- 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**
17alpha Ethinyl
- Decreases conversion to estrone (oxidative metabolism)
- Blocks 17B hydroxysteroid dehydrogenase
- Increases oral bioavailability by 15-20x
Ester Derivatives
- Administered IM
- Long estrogen effects over weeks
- Slowly hydrolyzed in vivo and at injection site
Conjugated Estrogens
-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)
Ethinyl-estradiol Comments
- Semi synthetic
- Oral Contraception
SERM
- Used in hormone replacement therapy
- Agonist in bone
- Antagonist in breast/endometrium
SERM Applications
- Treat estrogen-dependent breast cancer (Tamoxifen, Toremifen)
- Bone loss in postmenopause: Raloxoifene, Bazedoxifene
- Treat dyspareunia in postmenopause: Ospenifen (vaginal epithelium)
Antiestrogens
- 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)
Progestins
- Progesterone
- Rarely used therapeutically (poor oral bioavailability)
- Use progesterone agonists
- Use with estrogens for hormone replacement and as birth control
Two Progesterone Classes
- Progesterone agonists
2. Norethinedrone
Progesterone Agonists
- 21C backbone
- Highly selective
- Hormone replacement
- Derivatize rings B & D
Norethindone
- 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
2nd/3rd Generation Combinations
- More potent than estrones and decrease androgen activity
- Replace 18-methyl with an ethyl group
- EX: levonorgestrel, norgestimate
Treatments of Menopause
Estrogens • 17β-Estradiol • Conjugated estrogens • Esterified estrogens • Estropipate
Progestins
• Medroxyprogesterone acetate
• Micronized progesterone
Selective estrogen receptor modulators (SERMs)
• Bazedoxifene
• Ospemifene
