Estrogens Natural Estrogens Estradiol - - Estriol Most Potent Its quinone is carcinogenic Distance = 10.9 A - Semi-Synthetic Estrogens Estrone Major in Urine Weakest - - Ethinyl Estradiol Major in Blood Stable in GIT Responsible for 1/3 of activity Used in HRT - - 100 times more potent than Estradiol COCs Mestranol - - Estrogens Only the TRANS isomer - High H2O Solubility (IV) - Distance = 12.1 A - Ttt. Of Prostate Cancer - Not Used Anymore - - Estramustine Sod. Phosphate Estradiol + Cyclopentyl Propionic Acid Prepared by Drastic conditions then mild hydrolysis - - Mutual targeted prodrug Ttt. Of Prostate Cancer Converted by Phosphatase & Carbamidase Anti-androgen + DNA Alkylating Agent Premarin (Estrone & Equilin Sulfate) - - Attenuated Estrogens → HRT Short Duration + Weak Activity Anti-Estrogens Synthetic Non-Steroidal Estrogens Trans-DES Fosfosterol - Methyl Prodrug of EE COCs Estradiol Cypionate Full Antagonists Fulvestrant - SERMs Clomiphene Z - Tamoxifen Ttt. Of Breast cancer in POSTmenopausa l women - Oral Racemate - Antagonist in hypothalamus & pituitary - - SERD - - I.M. once monthly Partial Agonist in ovaries - Ttt. Of Infertility - Causes PCOS, OHS & Multiple Births Aromatase Inhibitors - - Raloxifene Agonist in Bones, Uterus & Liver - Agonist in Bones ONLY Antagonist in Breast - Antagonist in Breast & Uterus Ttt. Of Breast Cancer in PRE- and POSTmenopausal women Major Met. → inactive (N-dealkylation) Minor Met. → Active → P-Hydroxylation (Afimoxifene) - Amino Ethyl Chain → Essential - Halogenation of Amino Ethyl Chain → ↓↓ Activity - Safer than T but high risk of clots - Nitrogen of Raloxifene + Asparagine → Prevent Helix from Folding → Antagonistic Activity - Ttt. & Prevention of Postmenopausal Osteoporosis Exmestane Letrozole Irreversible = Suicidal Inhibitor - Reversible STEROIDAL - NONsteroidal N-4 Nitrogen of the triazole ring interacts with the heme iron atom of Aromatase Estrogens SAR: Essential Modifications Enhances Activity Alkylation Decreases Activity - Estrogen Binding Site is spacious and hydrophobic Phenolic group of estradiol is positioned in a narrow slot The interaction of Raloxifene with Asparagine dictates its Antagonistic Activity Unsaturation Decreases Activity NOT Essential Progestins Progesterone Derivatives Dydrogesterone Progester one caproate - 9 Beta + 10 Alpha + Extra = - Atypical → Does NOT inhibit ovulation → NO CONTRACEPTION - Ttt. Of Abortion Irregular Cycles - + Estrogens → HRT + - Medroxyproge sterone Acetate (MPA) 17alpha Ester → Depot injectio n Prepar ation Megesterol Acetate (MGA) ORAL or Injection POP Ttt. Of Breast & Endometrial Cancer Ring D protect ion ORAL Androstane Progestin Ethisterone Estrane Progestins Norethistero ne Lynestrenol L-Norgestrel - - AntiProgestin Mifepristo ne (Norethindrone) - Ttt. Of LATE stages of Breast Cancer with Aromata se inhibitor s Weak Androge nic Activity - ORAL COC - Metaboliz ed at 3-on- 4-en Strong Progestin Action Prodrug of NE ORAL POP - - NO androge nic effect ORAL COC 18 Beta Ethyl Gp Abortifacient RACEMA TE has 50% Activity Androgens Natural Androgens Testosteron e - Stanol on Synthetic ORAL Androgens Methyl Testosterone Fluoxymesetrone Mesterolone (Proviron) WEAK oral activity Mnemonic: Fo2 1 Mester Mohamed Tayar Warda HRT Propionate or - Ring - Ring D - Alpha Cypionate Esters → D Protection Methyl at Parenteral Prodrugs Protection Carbon 1 by 17-alpha - 9-alpha Fluoro - ANABOLIC methyl → ↑↑ Activity - Stanolon Deriv. ANDROGENIC Anti-Estrogen Danazol (Anti-GnRH + Anti-Estrogen) - Anabolic Steroids Ethinyl Testosterone + Isoxazole ring Steroidogenesis Inhibitor on Ovaries + Pituitary Ttt. Of Endometriosis + Fibrocystic Breast Disease Weak Progesterone + Androgenic Activity Stanzolo l Oxymester one Methenolo ne Okht Stan btshrb Meth Pyrazole Ring - 4 Delta-1 Hydroxy Mesterolone Gp (or Chloro) → ↑↑ Activity Estrane Anabolic Steroids Nandrol Norethandro one lone - Nortestosterone - IM Decanoate Ester Liver Tumor Impotence in Men CHD Anti-Androgens (5-alpha reductase inhibitors) Finasteride - Azasteroid Irreversible inhibitor by binding to Nicotinamide moiety of NADPH Progestins SAR: NOT Essential C-17 Esters Prolong Activity Increased Activity Essential Estrane Progestins SAR If removed → ↑↑ Progestogenic Activity while ↓↓ Androgenic Activity If Ethyl → Increased Activity Essential If Saturated → Androgenic Activity Mifepristone SAR Responsible for Antagonistic Activity If substituted with METHYL or VINYL → Agonist Phenyl Group with P- Fluoro or CF3 → ↑↑ SELECTIVITY Androgens & Anabolic Steroids SAR Carbonyl = Eliminates Activity Esterification = Prodrug + Parenteral 17-alpha substitution → Orally Active Removal Increases Anabolic Activity Heterocyclic Rings Increases Anabolic Activity 5-alpha reduction → ↑↑ Activity 9-alpha fluoro → ↑↑ Activity