Chapter 11 Hormones(2)

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Chapter 11 Hormones(2)
Pei Yu College of Pharmacy Jinan University
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3.Steroid Hormones
3.1 Steroid Estrogen (???)3.2 Non-Steroidal
Estrogen Selective Estrogen Receptor
Modulator 3.3 Male Hormones Protein
Anabolic Hormones (??????) 3.4 Progestogen
Hormone (???) 3.5 Steroid Contraceptive agents
(???) 3.6 Anti-progestogen(??????) 3.7
Adrenocorticoids (???????)
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3.3 Male Hormones and Protein Anabolic
Hormones(??????)

• Male hormones have male activity and protein
  assimilation (??) activity.
• Some structure modified compounds which are
  called protein anabolic hormones(??????)have very
  weak male activity but strong protein
  assimilation activity.
• Anabolic hormones are drugs derived from the male
  sex hormone to promote growth or to help the body
  repair tissues weakened by severe illness or
  aging, and it subject to abuse to promote muscle
  mass in athletes.
• The purpose to modify male hormones is to acquire
  new protein anabolic hormones .

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Anabolic Hormones

• Promote protein anabolism(????)and reduce its
  catabolism(????).
• Enhance the procedures of protein synthesis from
  amino acid.
• Clinical uses of anabolic hormones are treating
  sickness asthenia(??), cacotrophia(????)of
  new-born and aged people, consume diseases,
  osteoporosis and gastric and duodenal ulcer
  (???????) etc .

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Side-effect of Anabolic Hormones

• Male activity is the main side-effect of anabolic
  hormones.
• Minor change of structure of Testosterone(??)can
  cause male activity decrease and anabolic
  activity increase.
• For example
• De-methyl on C-19
• Substitution on ring A
• Fused rings of ring A
• No anabolic hormones without male activity .

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A
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Common Male Hormones and Anabolic Hormones
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Testosterone Propionate(????)
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3
4

• Chemical name
• 17?-Hydroxyandrost-4-en-3-one propionate

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Structure of Testosterone Propionate

• Testosterone is a natural male hormones.
  Separated from male cow testis(??) in 1935.
• It is ?4-3-ketone and 17ß-hydroxyl compound, and
  here it is propionate.
• UV absorption.

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Absorption and Pharmacokinetics

• By oral Testosterone cannot be absorbed in
  gastrointestinal tract, but Testosterone
  Propionate oil solution has prolonged effect in
  vivo because it can be hydrolyzed and release
  Testosterone slowly.
• Testosterone propionate Pro-drug.

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Biotransformation

• The ratio of activity
• Dihydrotestosterone Testosterone
• ?4-Androstenedione(????) 150100 10

Dihydrotestosterone
5a-Reductase
Testosterone
17 ß- dehydrogenase
?4 Androstenedione
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Analogues of Testosterone

• The advantage of 17a-methyl analogue
• rapid oral absorption,
• fine bioavailability,
• can not be decomposed in liver.

valerate
undecylenate
Prolonged effect.
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Synthesis of Testosterone
Oppenauer
Dehydrotestosterone
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3.4 Progestogen Hormone(???)

• Progesterone(???) and 17a- hydroxy-progesterone
  are natural progestogens (???).
• Use together with estrogen hormones to keep
  female reproductive cycle and physiological
  character.
• The preparations of progestogen hormones combined
  with estrogen hormones are used as oral
  contraception agents(??????).
• Offset side-effects in estrogen replacement
  therapy.

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Progesterone(???)

• Chemical name Pregn-4-ene-3,20-dione

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Structure features
C-21-Steroids with ?4-3-ketone
Differences of structure
Progesterone 17ß-acetyl
Testosterone 17ß-hydroxyl
Testosterone (??)
Progesterone (???)
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17a-Substitute Progesterone( Oral )

• The first effective oral Progesterone drug is not
  derived from Progesterone, but a Testostrone
  analogue Ethisterone (???).
• When ethynyl(???) group at C-17? of Testostrone
  is added, its male activity lessened and
  progestogen activity strengthened, it can be
  orally used.

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• Then 17a-Hydroxyprogesterone was found during
  biosynthesis studies of cortical hormone. The
  activity of its acetate is only 1 of
  Norethisterone (???).
• 17a-Hydroxyprogesterone Caproate(???) has a
  prolonged activity, which oil injection can be
  used once a month .

No methyl
R -CH3 hydroxyprogesterone acetate R
-C5H11 hydroxyprogesterone caproate
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Medroxyprogesterone Acetate(??????)

• Chemical name
• (6 ? )-17-Hydroxy-6-methylpregn-4-ene-3,
  20-dione acetate

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Metabolism of Progesterone
Activity are lessened!
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Oral Potent Progestin(????)
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6
6

• The C-6 analogues

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Levonorgestrel(?????)
3.5 Steroid Contraceptive agents(???)

• Chemical name
• D-(-) 17?-Ethynyl-17?- hydroxy-18-methyl-estro
  -4-en-3-one

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• Chemical structure of Levonorgestrel is similar
  as Norethisterone (???) except C-13 ethyl
  substitution.
• Levonorgestrel(?????)is the active configuration
  of the drug, while Dextronorgestrel (?????) has
  no effect .

No methyl
D
L
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Synthesis of Levonorgestrel
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Mifepristone(????)
3.6 Anti-progestogen(??????)

• Chemical name
• 11?-4-(Dimethylamino)-phenyl-17?-hydroxy-17-
  (1-propynyl)estra-4, 9-dien-3-one

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Hormone, its excitomotor and antagonist(?????????
?)
synthesized excitomotor
Hormones
Hormone antagonist
pregnancy (hormone antagonist)
estrogen (hormone antagonist)
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Structure feature

• Compare with Norethisterone(???)
• C-9 ene
• 11 ?-4-(dimethylamino)-phenyl
• 17 propyne

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Use of Mifepristone

• Mifepristone is used as an abortifacient(???)i
  n the first two months of pregnancy, and in
  smaller doses as an emergency contraceptive(???).
• Medical termination of intrauterine
  pregnancies(?????)of up to 49-65 days
  gestation(??).
• Softening and dilatation of the cervix(?????)
  prior to mechanical cervical dilatation for
  pregnancy termination.
• Labor induction in fetal death in utero(????).

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SAR of Mifepristone
acetyl phenyl group can increase activity, while
short fatty series will turn inhibitor to
excitant.
Any substitute will decrease the activity.
If substitute moved to o- or m- position, it
will influence on double bond forming to lower
drug activity
Increase oral activity .
a- methyl, it will turn inhibitor to excitant.
Any substitute has no the activity.
methyl, methanol, or ester cant change
anti-corticosteroids activity .
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Metabolism of Mifepristone
N-demethyl
N-dedimethyl
Propynyl hydroxy
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Synthesis of Mifepristone
From Norethisterone, 8 steps
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3.7 Adrenocorticoids(???????)
Classification of adrenocorticoids
1.Mineralcorticoids(?????) Oxygen atoms do
not exist at C-11 and C-17 at the same
time. Aldosterone(???) , Deoxycorticosterone(?????
) 2.Glucocorticoids(?????) Oxygen atoms do
exist at C-11 and C-17 at the same time.
Hydrocortisone(?????), Cortisone(???)
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Main Natural Adrenocorticoids
Glucocorticoids
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11
Mineralcorticoids
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Structural of Adrenocorticoids(???????)
17
11

• Pregnane backbone with ?4-3, 20-di-one 11,17,
  21- hydroxyls.

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Mineralocorticoids(?????)

• Aldosterone (???) and deoxycorticosterone(?????).
• Mineralocorticoids can regulate water and salt
  metabolism and keep the electrolyte balance in
  vivo, but it isnt used in clinic widely.
• Its metabolism antagonists is used as
  hydragogues(???).

Aldosterone (???)
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Glucocorticoids(?????)

• Most of corticoids are Glucocorticoids.
• Glucocorticoids are important drugs.
• They have direct relationship with metabolism of
  sugar, fat, protein and body growth.
• Glucocorticoids still keep influence on
  metabolism of water and salt more or less.

Hydrocortisone (?????)
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Hydrocortisone(?????)

• Chemical name
• 11?, 17?, 21-Trihydroxypregn-4-ene-3,
  20-dione

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Biosynthesis

• Endogenous(???)Hydrocortisone is biosynthesized
  from cholesterol(???)via 17a-hydroxyl
  progesterone( 17a-?????)by enzyme catalysis .

17a-Hydroxyl-Progesterone
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Metabolism
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?4, 3-????
C-20????
?4, 3-ketone are reduced
C-20 side-chain is cut down
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• How to modify the Glucocorticoids?
• Modification at C-21.
• Modification at C-1.

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Modification at C-21

• Only C-21 hydroxyl can be esterified, other
  hydroxyl cant be esterified easily because of
  steric hindrance .
• C-11 Hydroxyl group is blocked by C-10 and C-18
  methyl group.
• C-17 hydroxyl group is blocked by side chain.

Steric hindrance
Esterify easily
Esterify hardly
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Hydrocortisone C-21 esterified analogues
Drug Name
Substituent group
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Modification at C1

• Hydroprednisone acetate(??????) can be prepared
  by dehydrogenation at C1-C2 to introduce double
  bond in the ring A from Hydrocortisone acetate.
• Its anti-inflammation activity is 4 times of the
  leading compound while its sodium retention (???)
  activity is not changed.

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Dexamethasone Acetate(??????)

• Chemical name
• 9-?-Fluoro-11?, 17?, 21-trihydroxypregna-16?-m
  ethylpregna-1, 4-diene-3,20- dione-21-acetate.

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Use of Dexamethasone

• Dexamethasone is a potent synthetic member of
  the
• glucocorticoid class of steroid hormones.
• It acts as an anti-inflammatory and
  immunosuppressant
• (?????).
• Its potency is about 20-30 times that of
  hydrocortisone
• (?????) and 4-5 times of prednisone(???).
• Shock 4 to 8 mg intravenously initially, repeat
  if
• necessary to a total dose of 24 mg.
• Autoimmune diseases and inflammations longterm
• therapy with 0.5 to 1.5 mg oral per day.
  Avoid more
• than 1.5 mg daily because of serious side
  effects.

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Structure feature

• All substituents on the pregnane(???) backbone.

Most important!
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Reaction with sodium sulfite

• Dexamethasone-21-sodium phosphate can react with
  sulfite hydrogen sodium to produce C-1
  sulphonation at ring A, which is a reaction on ?,
  ?-unsaturated ketones.

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The SAR of Dexamethasone
Double bond between C1 and C2 increases activity
of Glucocorticoid, not that of mineralocorticoid
Only ß-hydroxyl has activity
ahydroxyl, a-methyl , ß-methyl decrease
Mineralocorticoid activity, a-hydroxyl lower
Glucocorticoid activity a-methyl and ß-methyl
has no influence on Glucocorticoid activity.
a-fluorine will increase activity of
Glucocorticoid and Mineralocorticoid.
a-methyl has no effect on activity, but a-
fluorine will increase Glucocorticoid activity.
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Modification at C-9 position

• 9?-Fluorin hydrocortisone is the first famous
  cortical hormone, which was also discovered by
  chance.
• Its anti-inflammation activity was 10 times
  stronger than cortisol.

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Modification at C-16 position

• Introducing fluorin at C-9 with other groups at
  C-16 at same time will decrease effect of water
  and sodium retention.
• 16-Methyl Hydrocortisone increase the activity
  and stability.

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Modification at C-6 position

• Introducing fluorin at C-6 can prevent it from
  oxidation.
• It can only be used in the form of external
  preparation as anti-anaphylaxis(????)of skin.

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Stability of Dexamethasone Acetate

• Ring A, depending on different photocatalysed
  experimental conditions, the ?4-3-ketone of it
  can be transformed, including Ring B enlarged or
  shrinked compounds.

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• Ring B is steady.
• Ring C could be oxidized in solvent, influenced
  by temperature, free radical and UV.

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• Ring D, C-17 hydroxyl and ketone-hydroxyl groups
  are tautomeric(?????) under alkali catalysis, it
  is very sensitive (with oxygen or not).

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Synthesis of Dexamethasone
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Story of Dexamethasone

• Global market of Dexamethasone is shared by two
  international pharmaceutical companies French
  ROUSSEL and American UPJOHN before 1980s.
• Chinese TIANJIN pharmaceutical factory fighted
  with the two giants over three times, and finally
  monopolized the market successfully.

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Oppenauer Oxidation a gentle method for
oxidizing secondary alcohols to ketones.
It is the opposite of Meerwein-Ponndorf-Verley
reduction. The alcohol is oxidized with
Aluminium-tert.-butylate in excess acetone.
Mechanisim