Timmermann Flashcards
Labeling alpha or Beta
Number the cholesterol
All the cholesterol compounds we go over are cis or trans? meaning what?
All trans and its talking about the fusion of the rings
Cholestane skeleton?
Example?
Long side chain and 2 methyl on 13 and 10
18, 19 methyl
Cholesterol
6 carbons
Cholane?
Small sidechaine than cholestane 4 carbons
two methyls 18 19
Pregnane
Much smaller side chaine
Estrane nucleus
Absence of 19 carbon
Androstane
Practice
Cholesterol —>? Preg?
What is involved?
Summary of pathway
Where is aromatase involved?
What is armomatase involved in?
What are the biosynthetic steps for Estradiol from Androstenendione
—> Aromatase gives Estrone
17b-HSD —> Estradiol
Estrogens natural sources
- Ovaries
- Plcenta
- Adrenal cortex (males and females)
- Plants (flavoniods)
- Mare urine
Structure activity relationship of Estrogens
Estrane nucleus has no?
C19 carbons
Estrogens aromatic where?
A rings
esterogen group at 3 position?
Subject to?
What does this limit?
- Phenolic hydroxyl
- Subject to biotransformation, which limits the duration of action, sulfation and glucuronidation
Estradiol
rxn via sulfation and glucuronidation products
Estradiol sulfate and estradiol glucuronidate
3-hydroxyl group on estradiol is subject to ______ metabolism especially with ____ and to a lesser extent with?
What do these things cause?
- Phase II metabolism mostly with sulfation but also with glucuronidation
- Sulfation and Glucuronidation increase polarity and cause more renal elimination
What does an ether at the C3 position of an Estrogen cause?
2 things
- Ethers prolong the DOA by preventing sulfation and glucuronidation in vivo
- The ether derivatives are inactive prodrugs that require hepatic dealkylation for activity
Estrogens: 17 a group hydroxl
What happens at the 17b group and what enzyme causes it?
Hepatic oxidation by 17b-hydroxysteroid dehydrogenase
Makes a less active ketone and limits oral activity
Estrogens 17 alpha ethinylation
Blocks?
Permits?
Estrogens 17b OH esterifications
Provides?
Protects?
What happens in tissue?
Estrogens indications 4
Estrogen preparations
Estrogen preparations: Natural estrogens and their esters
Natural Estrogens: Estradiol
Amongst the natural?
Metabolic vulnerability?
Forms?
Natural Estrogens
Estrone
Activity compared to estradiol?
Conjugated Estrogens
Premarin
Saturation in the B ring?
What is important to note about the mixture?
Isolated from?
What form?
Sodium Estrone Sulfate
Conjugated estrogens have grreater water solubility- this is the form found in urine
PO, IM, IV
Synthetic Conjugated Estrogens
A and B
Hydrolysis of 3-sulfates via intestinal _____?
Forms?
Talking about premarin
What is premarin considered?
Esterified estrogens? Name it
What protects it?
Hydro or lipophilic?
Form?
Duration?
Estradiol valerate or estradiol cypionate
Which one is more lipophilic and why?
Cypionate because 17 B SC
Esterified estrogens
Estra-cyp
Semi-synthetic Estrogen preparations
Ethinyl estradiol
What is it?
Prodrug or active?
Important to note about the 17a?
What is it used as?
17 α-Ethinyl Estradiol 3-Methyl Ether (Mestranol)
Prodrug or active?
Synthetic lack ___ structure - ?
3 have estrgenic Agonist activity
Estrogenic antagonist activity
3 type then drugs
Diethylstilbestrol (DES)
Form of ____ with the __ and ___ ___
Two phenolic ___ are set the same ___ as in ____
Why is this important?
Synthetic Estrogenic Agonist
DES
A very ____ ____ estrogen
What Isomer is 10 x more potent than?
Formerly used to?
Now?
Two DES analogs?
Dienestrol (Synestrol)
What has been maintained?
Active in what wat? But how is it used primarily?
Chlorotrianisene
No free ___ which blocks what? This also means it can be what form?
Distance of what?
SAR summary
Feature essential for estrogenic activity 4 points
Modification where can enhance activity?
WHat provides the greatest activity?
Antiestrogens
Important in the modification of?
What are the two major groups?
Triphenylethylene Analogs
What structure is retained? But features what type of moeity that is critical for antiestrogenic activity?
Clomiphene
What isomer is the ant antagonist and what one is the agonist?
Clomphene
Employed to promote?
Form?
What SEs?
Tamoxifen
What isomer is used? What type of compound is it?
Used to treat?
form?
Selective estrogen Receptor Modulators
SERM
What are these trying to circumvent
SERMs
All approved drugs in this category exhibit?
Why have they been given the name SERM?
Raloxifene
What type of activity? And what two things does this help?
What effect on breast tissue?
No ___ effect on the uterus?
form?
Toremifene
Related to?
What reduces its anti-estrogenic potency?
Other SERMs in trials?
Fulvestrant and Acolbifene
Triazole ___ inhibitors
2 of them
Prevent what?
What type of inhibitors?
Role of aromatase?
Role of Aromatase in Cancer?
Block conversion of?
Control?
Aid in?
What binds heme in Anastrozole and Letrozole
Anastrozole
Specific?
Tx of?
Letrozole
What does it do?
Tx of? Second line to?
Exemestane?
What is it?
Reversible or irreversible?
Tx of?
Phytoestrogens?
Phytoestrogens
Soy isoflavone B-glycosides are?
Phytoestrogens
What activity do they have?
The two hydroxyl groups?
Tx of Phytoestrogens?
Where is the focus of progesterone drug in the pathway?
Nat sources of Progestin
4
What is an important note about synthesized progestterone?
Semi and Bio synthetic sources of progestins?
Indications for progestins?
Pregnane nucleus what are the important features? For derivates
Key progesterone functional groups
What do they do?
What are the two main progestin products?
Progestin Products: Progesterone and Derivatives
Starting at Nat Progestins then from there
Progesterone
Prometrium
Duration? Due to?
Where from?
What places are susceptible for metabolism?
Progesterone: Metabolism to?
What is added and different?
What does it get metabolized by?
Addition at 6 you should know whay its metabolized to
Progesterone metabolism due to reduction
what is the product and where are the changes
Progesterone
Progestasert
Despite?
17a-Hydroxyprogesterone what is it?
Where is it produced?
Where is 17a-Hydroxyprogesterone in the Steroid Hormone Syn pathway
17a-Hydroxyprogesterone
Metabolism
what is teh same and what is different in comparison to progesterone metabolism
What does this limit?
Blocking the Metabolism of 17a-Hydroxyprogesterone
Progestin Products: Progesterone Derivatives
3
Blocking 3-keto-4-ene metabolism and 6ahydroxyation
What aspects are improved?
Medroxyprogesterone Acetate
What SC is introduced? What does this cause?
Slow reduction of the keto and double bond 4-5
Medroxyprogesterone Acetate
at teh C6 position ___ is added and this decreases?
This blocks?
Medroxyprogesterone Acetate (Provera)
What does the liver do? Similar to ___ except for?
What is active?
What decreases reduction of 20-keto
Medroxyprogesterone Acetate
How is it active?
What types are ective how is this different?
What form provide contraception for 3 months?
Medroxyprogesterone Acetate
In Prempro
Used in combination with?
Megesterol Acetate
(Megace)
What on the B ring increases activtiy?
How much of oral dose is metabolized?
How does it differ from Medroxyprogesterone?
How does it block metabolism
Megesterol Acetate
Active in what form?
Acitivty similar to?
What decreases reduction of 20-keto?
Ethisterone and Analogues
_ derivative of what?
SAR summary of Progesterone and Derivatives
Progestational effects depend on wha 4 things
What mays it fit better to the receptor?
Alkene
SAR Summary of Progesterone and Derivatives Synthetic Mods
2 main mods and talk about their effects
Progestin Products
19-Norandrostane Derivatives
The rapid metabolism of progesterone triggered?
Key 19-Andro SAR
Androstane Nucleus without?
19-Norandrostane Derivative products
19-Norandrostane
SAR
What contribute to the androgenic/anabolic effects?
Readily metabolized to?
what is in the A ring?
19-Norandrostane
SAR at c17 what is added and what does it block?
Analogues with what are inactive?
19-Norandrostane
SAR at C17 Improving Progestational over Androgenic acitivty
What group here changes to more progestational?
Ethynyl
What does the 17 ethynyl 19-Norandrostane do ofr activity across the board?
17 ethylyl 19-Norandrostane products
7
Norethindrone
What blocks what?
Typically given?
Norethindrone Acetate Combipatch
Ester __? Metabolized where to form?
Prolonged action in what form?
Androstane Nuc
what are the parts?
C13 Ethyl Derivatives
All have what at C13?
All haev what at C17
Norgestrel and Levonorgestrel
Norgestimate
Desogestrel
Gestodene
SAR for 19-Norandrostane Derivatives
4
SAR for 19-Norandrostane Derivatives
Modifications
4 and what do they do
Other progestins to look at
Antiprogestin: Progesterone Receptor Antagonists
Mifepristine also known as?
What does it do?
How does it do it?
Key structural features of RU-486
Antagonism is mediated by?
