Clinical

Clinical
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MEDICINAL
LECTURE
12
CHEMISTRY-2
Activity of estrogens increases by:
● Methyl or ethyl at C11: ↑ affinity to receptor
● Ethinyl at C17α: protection of 17β-OH (oral)
● Equines, with 1 or 2 extra double bonds at ring B.
Activity of estrogens decreases by:
● Removal of Oxygen at C17.
● Epimerization of 17β-OH
● Any group at C1
Steroidal nucleus is not essential for activity. Many stilbene derivatives (especially trans isomers) have estrogenic activity.
steroids ‫ تكون‬estrogen receptors ‫ اللي بتشتغل على الـ‬compounds ‫مش الزم الـ‬
diethyl
stilbene: double bond
that is connected to 2
aromatic rings
phosphate prodrug of
diethyl stilbesterol
DIETHYL STILBESTEROL
phosphatase ‫● بيتكسر بإيه؟‬
‫ كل ما‬phosphate ‫● اتعمل ليه؟ الدوا كل ما فيه‬
)‫ أكتر (إلانزيم موجود بكمية أكتر‬cancer‫بيدخل خلية الـ‬
FOSFOSTEROL
● Trans is 14x more active due to similarity to estradiol (distance between the 2 OHs mimics estradiol)
● No longer used as an estrogen for women (cause bleeding).
● But used for treatment of prostate cancer in men (they are testosterone physiological antagonist).
: ANTAGONISTS ‫ أنواع من الـ‬3 ‫فيه‬
1- Physiological antagonists: Ach + adrenaline
2- Chemical antagonists: aminoglycosides + ampicillin
3- Pharmacological antagonists: sympathomimetic + parasympathomimetic
SERMs ← partial agonist : ‫ده اسم قديم ← الجديد‬
❶ IMPEDED ESTROGENS
● The classical impeded estrogen is Estriol.
● They interact with estrogen receptors but dissociate rapidly from receptor with no strong estrogenic effects.
● In ↑ local conc. → compete with (impede the access of) estradiol to receptor site → ↓ estradiol effect on cell
❷ SELECTIVE ESTROGEN RECEPTOR MODULATORS [SERM s]
Agents that bind to estrogen receptors but act either as agonists or antagonists in different tissues
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CLOMIPHENE CITRATE
BASE
+
citric acid
‫الكبيرة‬
ethyl
‫الصغيرة‬
‫ الكبيرة‬gp ‫الـ‬
‫ الصغيرة‬gp ‫الـ‬
Triphenyl
ethylene
clomiphene citrate
‫الكبيرة‬
‫الصغيرة‬
‫ الصغيرة‬gp ‫الـ‬
‫ ؟‬trans ‫ ولال‬cis ‫ازاي بعرف املركب‬
‫ ماسكة في‬atom ‫بقيس على حجم أول‬
‫ أكبر من‬Cl ‫ هنا الـ‬،double bond ‫الـ‬
trans (E) ‫ وبالتالي املركب‬،C ‫الـ‬
‫ الكبيرة‬gp ‫الـ‬
● Z isomer (cis): WEAK ESTROGEN (AGONIST)
Used as racemic mixture )‫(عشان ميأثرش على باقي الجسم‬
● E isomer (trans) : PURE ANTAGONIST
● Uses: ttt of Anovulatory Infertility: Taken orally to induce ovulation “Central effect” )‫ في الدماغ‬block receptor ← BBB‫(يعدي الـ‬
● ↑ doses: ↑↑ FSH → ↑ number of mature ova → MULTIBIRTH (SE)
● Can be used for men: ↑ Spermatogenesis.
1- ↑ Gonadorelin (GnRH) ‫محتاجة وقت طويل‬
2- ‫ حقنة‬FSH + LH
3- ↓ Estrogen (Block receptor)
↑
TAMOXIFEN DIHYDROGEN CITRATE
● ONLY Z isomer (cis) is used. )‫ بس‬receptor‫(ليه؟ عشان عايزين نقفل الـ‬
● Uses: ❶ Postmenopausal estrogen-receptor-positive breast cancer
(antagonist at breast tissue) “peripheral not central”
❷ Estrogen agonist effect at bones, lipid & uterus.
❸ ↑ HDL & ↓ LDL→ ↓ anginal pectoris & ↑ Ca deposition in bones →
Advantage for post menopausal women.
● SE: Uterine cancer (agonist at uterine tissue)
● Metabolism:
- MAJOR: N-demethylation → N-demethyltamoxifen
- MINOR: p-Hydroxylation → 4-hydroxytamoxifen → bind more
strongly to estrogen receptors > tamoxifen (additional binding group).
ethyl ‫ بدل‬methyl
Z antagonist on breast
E agonist on breast
‫الكبيرة‬
‫الكبيرة‬
‫الصغيرة‬
clomiphene‫ في الـ‬Cl ‫بدل الـ‬
‫الصغيرة‬
(
)
‫ ؟‬ANTAGONIST ‫ و‬AGONIST ‫ازاي نفس الدوا يكون‬
ّ
receptor ‫ ← الـ‬internalization to the nucleus ← drug-receptor complex ‫فيتكون‬
‫ ← الدوا بيمسك فيه‬nuclear ‫ نوعه‬receptor ‫الـ‬
‫ على حسب نوع الخلية ونوع‬activators or suppressors of gene transcription ‫ مع‬binding ‫ ← يحصل‬DNA ‫مبيشتغلش غير ملا يمسك في حتة معينة في الـ‬
suppressor ‫ بيبقى فيه‬breast ‫ بينما في الـ‬activators ‫ بيبقى فيه‬lipids ‫ والـ‬liver ‫ اللي فيها ← في العضم والـ‬suppressors ‫ أو الـ‬activators ‫الـ‬
RAOLXIFENE
↑ binding
● Antagonist on breast & uterus, agonist on bones & lipids.
N in cycle
∴ less dealkylation ● Used for prevention of osteoporosis in postmenopausal women
(↓ metabolism) ● ‫ بس ممكن يستخدم‬breast cancer‫ لعالج الـ‬approval ‫مخدش‬
longer duration
‫ اللي بيحوّل الرجالة ستات‬enzyme‫ هو الـ‬Aromatase
Aromatase (CYP19A1) enzyme converts ❶ andostendione to estrone & ❷ testosterone to estradiol.
↓ Aromatase → ttt of post-menopausal estrogen dependent breast cancer.
After menopause: estrone is not converted to estradiol but if so → breast cancer.
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A] ANDROSTENDIONE DERIVATIVES
STEROIDAL (IRREVERSIBLE)
[Suicidal inhibitors] = irreversible inhibition
(compete with androstenedione for active site of aromatase → block conversion of androgen to estrogen).
extra methyl
+ extra double bonds
PROTOTYPE
Androstendione+ 4-OH
4-HYDROXY ANDROSTENDIONE = FORMESTANE
EXMESTANE
B] TRIAZOLE DERIVATIVES
NON-STEROIDAL (REVERSIBLE)
[Competitive inhibitor of aromatase] = selective & reversible inhibition of the
conversion of testosterone to estradiol NOT androstendione to estrone.
‫ تمسك في الحديد اللي‬N ‫املركب فيه‬
CYP19A1 ‫ بتاع‬cofactor ‫هو‬
‫دي اللي هتمسك‬
‫دي معندهاش‬
lone pair
spacer
‫الزم الكربون متكونش‬
‫ماسكة في أي هيدروجين‬
triazole (it could
triazole
spacer
also be imidazole)
‫دي وجودها من‬
‫عدمه مش فارق‬
aromatic
area
aromatic area
ANASTRAZOLE
:‫أي دوا في العيلة دي الزم فيه شروط‬
1) Triazole or imidazole
2) Carbon spacer
3) Aromatic area
4) Carbon carrying CN
must not have Hs
LETROZOLE
→ Synthetic (like progesterone in action)
"‫ بتاع الحمل‬، ‫"األم‬
PROGESTERONE
→ Natural
Female sex hormone secreted by ❶ Corpus luteum & ❷ placenta ( ‫) لو حصل حمل‬
● Therapeutic uses & pharmacological actions:
❶ ↓ sensetivity of uterus to contraction (oxytocin) → maintainance of pregnancy.
❷ Natural contraceptive: Prevent ovulation during pregnancy (↓LH) & ↑ viscosity of vaginal
mucus → hinder passing of sperms “hostile environment”.
❸ Maintain normal bleeding (ttt of dysmenorrhea, endometriosis & amenorrhea)
❹ Maintain pregnancy so used in abortion caused by progesterone deficiency “anti-abortion”
● Disadvantages of progesterone:
Pregn-4-en-3,20 dione
❶ Not taken orally due to rapid degradation in liver (1St pass effect).
“by 20,22 desmolase
(CYP11N1)”
❷ If taken during pregnancy → Virilization (masculization) of female foetus. ‫ ألندروجين‬metabolism ‫يحصلله‬
:‫ملحوظة‬
Estorgen is not given alone in contraception, why?
❷ SE: Na & H₂O retention ❶ Needs ↑ doses → Cancer risk
❸ Blood clotting abnormalities.
6
Abortion marker
major metabolite
excreted in urine
‫أهم واحد‬
5β-pregnandiol
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α-
A] PREGNANE DERIVATIVES
Usually esters are used as the parent 17α-hydroxy progesterone is inactive (by 7,20-desmolase → androgens)
Esters sterically hinder keto reduction at C20
I.M.
Long duration
I.M.
Short duration
1st pass effect ‫ عشان‬oral ‫مش‬
embolism ‫ عشان‬I.V. ‫مش‬
7a-HYDROXYPROGESTERONE
HEXANOATE (CAPROATE)
7a-ACETOXYPROGESTERONE
: Oral
: I.M.
6α-methyl
(3 months)
hydroxylation ‫مبيحصلش‬
MEDROXYPROGESTERONE
ACETATE
or 17α-hydroxyprogesterone ACETATE
α
β
DYDROGESTERONE
MEGESTEROL ACETATE
- Retroprogesterone derivative. )‫(املقلوب‬
- 9β, 10α instead of 9α, 10β
- No virilization ← ‫ مبيشتغلش عليه‬17,20-desmolase
- No androgenic & estrogenic actions.
- Maintain pregnancy (anti-abortion)
- Oral & I.M.
- Not metabolized due to CH₃ in 6
- Double bond at 6,7 → ↑ activity
- ORAL suspension for breast & endometrial cancer.
B] ESTRANE DERIVATIVES
=D ‫المرة الجاية‬
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