Progesterone

Intended Learning Outcomes

• Studying Mechanism of action, SAR and synthesis of Hormones

• Classify hormones and understand the difference between different classes.
• Link between essential pharmacophoric features of hormones and their activity
(Structure-Activity Relationship).
• Suggest structural changes to drugs in order to modulate their pharmacokinetic
and pharmacodynamic properties.

2
Progesterone

Therapeutic uses and pharmacological actions:

• It  sensetivity of uterus to contraction to facilitate implantation of fertilized
ovum  maintainance of pregnancy.
• Prevent ovulation during pregnancy & Thickening the cervical secretions.
• Maintain normal bleeding  used for dysmenorrhea, endometriosis,
functional uterine bleeding and amenorrhea. (Endometriosis: condition in
women in which endometrial like cells appear and flourish in areas outside
the uterine cavity, most commonly on the ovaries).
• Treatment of threatened and habitual abortion.
Progesterone

Disadvantages of progesterone:

• Very weak orally due to rapid degradation in liver.

• Virilization (masculization) of female fetus because it may give androstene
dione then testosterone.
Progesterone

Therapeutic uses

• Amenorrhea, Diagnosis of pregnancy, As contraceptives in

combination with estrogens.
• Habitual and Threatened abortion, Excessive uterine
bleeding, Reduction of the risk of endometrial cancer from
postmenopausal estrogens, Breast or Endometrial Carcinoma.
Dydrogesterone (Duphaston)

• due to change in configuration of → distortion of three dimensional

configuration of progesterone(Twisting)→ orally active & no virilization
of female fetus
• It has no contraceptive property as no feed back mechanism on LH.
• Uses : threatened & habitual abortion.
17--Hydroxyprogesterone derivatives
Long duration with hindered metabolism and depot action

17-Hydroxyprogesterone
17-Acetoxyprogesterone
hexanoate (caproate)

O O

OCOCH3 OCO(CH2)4CH3

O
O

Long duration
Contraceptive Parentrally not orally due to 1st
pass effect
 Medroxyprogesterone acetate
Megesterol acetate
(Depo-provera®)

 Taken by injection / 3months (long

duration).
 Active orally as tablets
 Extra double bond at C6 → twisting
 Makes hostile medium for fertilization
(by ↑ viscosity of vaginal fluids making it (change) of skeleton so taken orally.
difficult for sperms to move to fertilize
ovum).
 progesterone-only contraceptive
Estrane Progestins
With Some Estrane features and Progestrogenic Action

Ethisterone Norethisterone
(17α-ethynyltestosterone) [norethindrone]

17-Ethynyl-17-hydroxyandrost-4-en-3-one
 It was synthesized to find an orally active 5- 10 times more progestational activity
androgen but late it is proved to be an
effective oral progestin and used in
treatment of menstrual dysfunctions.
Estrane Progestins
With Some Estrane features and Progestrogenic Action

Lynesterol L-Norgestrel

Prodrug to Norethisterone used in Better oral bioavailability due to angular

treatment of menstrual dysfunctions. ethyl
Oral progesterone only-type
contraceptive.
(l) Not (d) is the active isomer
Please Keep in Mind That:
Progesterone Antagonist

Mifepristone H3C
N
H3C OH
CH3

Uses: O

• Antiprogesterone used as abortifacient with success 84 %

(while PGF2α: 100 % success).
• It is used as abortifacient in the first two months of
pregnancy, and in smaller doses as an emergency
contraceptive.
Progesterone Antagonist

Misoprostol (Cytotec®)

• Misoprostol is a synthetic prostaglandin E1 (PGE1)

analogue.
• Misoprostol is commonly used for labor induction. It
causes uterine contractions and the ripening of the
cervix.
• It may cause uterine rupture and death.
Birth Control (Contraception)

(1)-Combined:(progesterone /estrogen): either orally or by injection.

(by –vefeed back on FSH & LH → prevent formation of mature ovum.)
Oral:e.g. Progestin: (Norethidrone) + Estrogen:(Ethinylestradiol)
Injection:with longer duration (ester form)
e.g. : Estrogen: Estradiol cypionate.+Progestin:Norethidroneacetate
Birth Control (Contraception)

(2)-Progestine-only type contraceptives:

Medroxyprogesterone acetate( Depo-proveraR): [makes –vefeed back of
gonadotropins] & viscous cervical mucous
(3)-Implants:impregnated in L-NorgesterelButanoate( LNB) ( up to 5 years).
Androgens
Testosterone
Testosterone

They have two functions:

• Androgenic: normal reproduction, sexual performance ability, development and

maintenance of male sex organs and 2ry male sex characters (hair, voice …………)
• Anabolic: precipitation of proteins, water& salts in muscles→ muscle weight.
N.B:They are synthesized mainly in testes from cholesterol and at lesser amount by adrenal
cortex and the ovary in female.
Testosterone

In ♀: Androgen is anti-estrogen.
↑ in testosterone:
• hyper sexuality in ♂.
• prostate cancer in ♂.
• hirsutismin ♀(all treated by antiandrogen).
↓ in testosterone:
• Undescending testes: remain in abdomen (treated by LH).
• Hypogonadism or eunuchism: impotence (treated by testosterone).
• Oligospermia: low sperm count (treated by FSH).
Metabolism
Natural Androgens
Very weak oral activity

Testosterone 5α DHT (Stanolon)

Potent Androgenic and anabolic

Potent Androgenic and anabolic activity activity with weak oral activity
with weak oral activity due to inactive 5 times more active
metabolites
Esters of Testosterone

• Esters of testosterone are formed by esterification of the 17-hydroxy

gp. E.g. propionate (Sustanon), enanthate and the cypionate.
• Enanthate and the cypionate ,they are PRODRUGS with slow hydrolysis
of the ester in the vivo and release of free testosterone.
Esters of Testosterone

Testosterone Cypionate Testosterone 17-enanthate

Prolonged duration by Injection

Semisynthetic androgens (Orally active)
Highly Androgenic and Anabolic

17α-methyl testosterone Fluoxymesterone Mesterolone(Proviron)

Metabolic stable  orally C11- OH , C9-F   anabolic -CH3   Oral activity and
active by 20 times and androgenic by retard hepatic metabolism
Has androgenic and anabolic 10 times activity
activity.
Mainly for Oligospermia and Male Infertility
Anabolic steroids

S.E. Prostate Cancer and Male

Oxymetholone Norethandrolone

impotence
Nandrolone esters Stanazolol

 By I.M  Slow hydrolysis

Anabolic steroids
Androgens
Attenuated androgens
(compounds used for female disorders)

 Isoxazole derivative of ethisterone [17-ethinyl testosterone]

 Weak androgenic and anabolic with some antiestrogenic activity and
progesterone receptor modulator leading to decrease in Estrogen and some
Progesterone (Antigonadotropin)
 Used for endometriosis
 S.E. Masculization and Hairsutism
Androgen antagonist
Androgen Antagonists

In males: Benign prostate hypertrophy (BPH)& Prostate

cancer &Early puberty.
In females: hirsutism ( testosterone) and acne.
Androgen Antagonists

[i] Blockers of androgen receptors

Steroidal antiandrogen Non Steroidal antiandrogen
Cyproterone acetate (Androcur®) Flutamide [ Eulexin®]

F3C
O2N NH
O

 Compete with DHT for human prostate

Suppresses gonadotropin release and bind with  androgen receptor.
affinity to androgen receptor.  Used in combination with other drugs for
metastatic prostate cancer.
Androgen Antagonists

[ii] Androgen biosynthesis inhibitors

Finasteride (Proscar®) Dutasteride (Avodart®)

 Inhibits 5-reductase  prevent conversion of testosterone to 5-DHT

 Used for Benign prostate hypertrophy (BPH) and alopecia in male
Corticosteroids
Corticosteroids

• They are gluco and mineralocoticoids and secreted by adrenal cortex

of adrenal gland
Glucocorticoid Mineralocorticoid
 Regulate CHO, lipid and protein  They maintain water and
biosynthesis and metabolism. electrolyte balance by  Na
  inflammation & suppress reabsorption and  K, H
immunity. secretion.
 Cortisol is the most potent  Aldosterone is the most potent
endogenous hydrocortisone. endogenous hydrocortisone
Natural Corticosteroids

Cortisone Hydrocortisone Aldosterone

 Used orally or I.M as 21 acetate  Hydrocortisone is considered as is considered as the standard

ester. the standard adrenocorticoid  mineralocorticoid
 Acetate ester show  stability and since anti-inflammatory : Na With High Na and Water
longer duration so smaller dose retention is 1:1 retention
used
Glucocorticoids
Uses of glucocorticoids

1- asthma
2- immunosuppressant
3-antiallergic (if allergy is topically or in case of anaphylaxis)
4-rheumatoid arthritis
5- adjuvant therapy for cancer& hepatitis
6-antiemetic
N.B. glucocorticoids ↓ PLA2 → anti inflammatory activity.
Glucocorticoids
Side effects

1)  Na retention and K excretion.

2) Negative nitrogen balance,  gastric acidity, edema.
3) Not used for long term on the eye as they ↑ I.O.P.
Glucocorticoids
Analogs with high glucocorticoid and low mineralocorticoid
1-Dehydro derivatives (∆1)
Prednisone Prednisolone

1-dehydro cortisone 1-dehydro derv. of hydrocortisone

 They are more potent antirheumatic and antiallergenic Due to 1-double

bond agents than hydrocortisone  used in smaller doses.
 Fewer side effects  used for long period [GIT hazard].
Glucocorticoids
Analogs with high glucocorticoid and low mineralocorticoid
1-Dehydro derivatives ∆1 + 9 α-fluoro
Triamcinolone Dexmethazone Betamethazone

 Has glucocorticoid activity

 Slightly more active than
equivalent to prednisolone but
 Has 5-7 times the anti- dexamethazone.
with  mineralocorticoid.
inflammatory potency of  Used in treatment of
 In combination with folic acid
prednisolone. rheumatic diseases and
antagonist  treatment of
dermatologic disorders.
psoriasis.
Beclomethasone Fluticasone

 9-chloro-betamethzone.
 Potent glucocorticoid.
 Propionate derv.
 Dipropionate derv.
Used topically by Nasal
Used topically by
inhalation
inhalation for asthma and
rhinitis.
 Budesonide Mometasone

 Hemiketal for better

penetration
 Used topically
 Used in nebulizer for
Dermatology
treatment of COPD
 Used in asthmatic attacks.
Mineralocorticoid activity
9-fluoro analog of hydrocortisone

Fludrocortisone • 11 times more potent

than cortisone
acetate but
mineralocorticoid
activity is increased
300- 800 times.
• Orally used as 21
acetate derivative for
mineralocorticoid
replacement therapy
in Addison's disease.
SAR
Inhibitors of adrenocorticoid biosynthesis

• Used in Cushing syndrome

• Aminoglutethimide has aromatase inhibitory activity and used in breast
cancer also
OH

NC

HO
O

Trilostane Aminoglutethimide
Peptide Hormones
Peptide Hormones

 They are formed from amino acids by linking the -

COOH gp of an amino acid to the  -amino gp of
another one.
 Peptides are written with the residue having the free
NH2 gp on the left [N-terminus] & free COOH gp on the
right [C-terminus].
Peptide Hormones

 Peptidomimetics : are compounds that mimic the

action of peptides, they have improved
pharmacokinetics and pharmacodynamics, more
difficult to degrade by proteolytic enzymes than
peptides, which have short duration → long t½.
Peptide Hormones

• All natural amino acids are known as L-amino acids as they are
configurationally related to L-glyceraldehyde
R CH2OH
H H C
C
H2N COOH HO CHO

L-amino acid L-glyceraldehyde

• Peptides are written with the residue having the free NH2 gp on
the left [N-terminus], & free COOH gp on the right [C-terminus].
• E.g.1 : Alanyl-glycine N-terminus C- terminus
H2N ala-gly-COOH
Chemical Methodology for Decreasing
Proteolysis (peptidomimetics)

• 1-Replacing the L-residue with its enantiomer, the D-amino acid or

another D-residue. Many peptidases are unable to cleave at peptide
bonds consisting of a “fraudulent” D-amino acid.
• 2- Replacement of an L-amino acid with L-proline.
• 3- N-methylation of the amide nitrogen.
• 4- The introduction of pseudo (ψ) peptide bonds (amide bond
surrogates).
Peptide Hormones

1. Small peptides
Gonadorelins, Oxytocin & Vasopressin.
2. Poly peptides
Corticotropins, Calcitonin.
3. Proteins
Prolactin, Growth hormone.
4. Glycoprotein
Thyrotropins, Gonadotropins.
Gonadotropin-Releasing Hormone (GnRH)

Tyr5-Gly6
GnRH can be degraded by
enzymatic cleavage
between Tyr5-Gly6 and Pro9-Gly10
Pro9-Gly10

GnRH is a decapeptide that causes the release of the gonadotropins,

luteinizing hormone (LH) and follicle-stimulating hormone (FSH), from the
anterior pituitary gland.
Gonadotropin-Releasing Hormone (GnRH)

• If Gly6 is replaced with certain D-amino acids, as well as with changes in

the peptide C terminus, they generally are less susceptible to proteolytic
enzymes. For that reason, they are referred to as superagonists.

• In therapeutic (pharmacological) doses, GnRH superagonists: block

implantation of the fertilized egg, cause luteolysis of the corpus luteum,
and can act as postcoital contraceptive agents (although not approved
for this latter use).
Gonadotropin-Releasing Hormone (GnRH)

• This antifertility effect has been attributed to the fact that GnRH must
be administered in a low-dose, pulsatile manner for it to be
therapeutically effective as a fertility agent. Natural GnRH release
from the hypothalamus occurs in a pulsatile manner.
• When a superagonist is administered in pharmacological doses each
day, LH and FSH levels will initially rise (for 2 weeks: initial “flare-up”
of the original symptoms) but then begin to fall because of target
tissue desensitization/down regulation of pituitary GnRH receptors.
GnRH superagonists

Leuprolide acetate, a synthetic nonapeptide analogue of GnRH

(superagonist: 15x more potent than GnRH).
Goserelin Acetate:. Synthetic superagonist nonapeptide analogue of GnRH.
Nafarelin: decapeptide superagonist..
Peptide Hormones
1. Oxytocin
NH 2
3
1 Cys Try Ile
Uses S
S
6 Cys Asn Gln 4

↑ the uterine contraction during labor

Pro Leu Gly COOH
8

(parturition).
 Causes ejection of milk from mammary gland.
 Drug of choice to induce labor
Peptide Hormones
1. Oxytocin

SAR

 The cyclic 6 peptide contains 20 atoms, any change

diminishes activity NH 2
3

 Gly1 instead of Cys : decresases potency, increases

1 Cys Try Ile
S
duration due to gradual release. S
6 Cys Asn Gln 4

Pro Leu Gly COOH

8
Peptide Hormones
2. Vasopressin [ADH]

 Increases the uptake of water by osmosis (Antidiuretic

action)
 Promotes the contraction of arterioles and capillaries so
increase the blood pressure (vasopressor)
NH2
3
1 Cys Try Phe
S
S
6 Cys Asn Gln 4

Pro Arg Gly COOH

8
Peptide Hormones
2. Vasopressin [ADH]
SAR
 Lypressin (Lys8 instead of Arg ) has the
same vasopressor, ADH activity but more
stable
 Ornipressin (Orn8 instead of Arg) : increases
vasopressor activity by 10 times 1
NH2
Cys Try
3
Phe

 3- Desmopressin (1- desamino-8-D-Arg): S

S
increases anti diuretic activity by 250 times 6 Cys Asn Gln 4

(used in diabetes insipidus) Pro Arg

8
Gly COOH
Thyroid Hormones
Thyroid hormones

 The thyroid gland is the source of two hormones,

thyroxine (T4) and triiodothyronine (T3).

 Both are vital for normal growth and development and

control essential functions, such as energy metabolism
and protein synthesis.
Thyroid hormones

 The thyroid gland also contains two important

iodinated amino acids; diiodotyrosine (DIT) and
monoiodotyrosine (MIT).

 Anti-thyroid compounds: They are compounds that act

within the gland to inhibit the biosynthesis of the
thyroid hormone
Anti-Thyroid Compounds

1. Iodide:

 Iodide, as Lugol's solution (strong iodine solution) or as

saturated potassium iodide solution.
 It inhibits the release of thyroid hormones into the
circulation since it increases the concentration of iodide in
blood and thus inhibits the active uptake of iodide
Anti-Thyroid Compounds

2. Radioactive iodine:

 used in the treatment of hyperthyroidism and in the

management of thyroid carcinoma.
 It causes localized damage or destruction of thyroid gland
without injuring the nearly tissue or organ.
Anti-Thyroid Compounds
Thioureylenes [Thioamide]
1. Propyl thiouracil 2. Methimazole 3. Carbimazole
O O
HN HN N CH N
3 N
O CH3
S N S S
H
M.O.A.: Inhibit the peroxidase enzymes (TPO) responsible for
iodination of tyrosine residues and the coupling of iodotyrosine
residues to form iodothyronines.
 it is prodrug, giving
methimazole in vivo,
to mask bitter taste
 Padlet Activity

• https://padlet.com/eamer3/what-do-you-think-happens-in-our-bodies-
when-progesterone-le-5x5i9sd0kdpfpds6
Structure Identification Activity
 17-Acetoxyprogesterone 17-Hydroxyprogesterone
O
hexanoate O
OCOCH3
OCO(CH2)4CH3

O O
Medroxyprogesterone acetate Megesterol acetate Ethisterone

Norethisterone Lynesterol L-Norgestrel

Mifepristone Misoprostol (Cytotec®) Testosterone
H3C
N
H3C OH
CH3

5α DHT Testosterone Cypionate Testosterone 17-enanthate

17α-methyl testosterone Fluoxymesterone Mesterolone(Proviron)

 Oxymetholone Norethandrolone Nandrolone esters

Stanazolol Cyproterone acetate

Flutamide Finasteride (Proscar®) Dutasteride (Avodart®)

Cortisone Hydrocortisone Aldosterone

Prednisone Prednisolone
Triamcinolone Dexmethazone Betamethazone

Fludrocortisone
1. Propyl thiouracil 2. Methimazole 3. Carbimazole

O O
HN HN N CH N
3 N
O CH3
S N S S
H
References

• Foye's Principles of Medicinal Chemistry: Williams PhD, David A.

• Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical
Chemistry
Faculty of
Pharmacy