PCOL826B_2023_WONDRAK_steroid lecture 3.pdf

Steroid lecture 3: Medicinal Chemistry of Estrogens and Progestins for Hormonal Contraception PCOL 826B [email protected] 68 Current Contraceptive Method Used by U.S. Women Who Are Using Contraception William D. Mosher and Jo Jones, "Use of Contraception in the United States: 1982-2008,"...

Steroid lecture 3: Medicinal Chemistry of Estrogens and Progestins for Hormonal Contraception PCOL 826B [email protected] 68 Current Contraceptive Method Used by U.S. Women Who Are Using Contraception William D. Mosher and Jo Jones, "Use of Contraception in the United States: 1982-2008," Vital and Health Statistics 23, no. 29 (2010). http://www.prb.org/Publications/Articles/2012/us-contraceptives.aspx 69 Combination oral contraceptives (COC) estrogen natural cycle progestin monophasic sequential multiphasic biphasic triphasic progestin only 70 Components of representative oral contraceptives EE 71 Oral contraceptives: Adverse and beneficial effects Mild adverse effects: nausea, headache (with exacerbation of migraine), breakthrough bleeding, weight gain; edema (dependent on estrogen dose), estrogen-induced fibrinogen elevation, antithrombin III reduction, increased blood coagulability, increased skin pigmentation; acne [with androgenic progestins (19-nortestosterone derivatives)]; prolonged amenorrhea after cessation of administration. Severe adverse effects: Vascular effects: Venous thromboembolism (VTE): approx. three fold increased risk of thromboembolism Myocardial infarction: higher risk in women with obesity, hypertension, diabetes, hyperlipoproteinemia; particularly in smokers; [HDL lowered, LDL elevated due to androgenic activity of progestins; increased blood coagulability due to estrogen component] cerebrovascular disease: thrombotic or hemorrhagic stroke others: cholestastic jaundice (17-alkyl substituted steroids), etc. Beneficial effects: - Reduced endometrial and ovarian cancer incidence - Acne improvement with high estrogen doses (and nonandogenic progestins). 72 Progesterone and Progestin Drugs Progesterone is a C21-steroid with a 4-ene-3one group and a ketone function at C-20. Produced by the corpus luteum in the ovary during the luteal phase of the menstrual cycle; also produced by placenta during pregnancy. 73 Progestin hormonal profile 74 Oral contraceptives I 75 Rapid Metabolic Deactivation of Progesterone Plasma half life: 5-10 min due to rapid hepatic metabolism. Mini-SAR Substituents at carbons 17a and 6 act as metabolic shields improving oral availability. Removal of C19 angular methyl group enhances progestin potency. Acetylation of 17a-hydroxyl group increases duration of action. 76 Progestogenic drug diversity Progestin optimization: Modulating androgenic and antimineralocorticoid activity Progesterone and progestins are promiscuous steroid hormone ligands that target a multitude of nuclear steroid receptors. Using medicinal chemistry progestins with optimized binding profile have been designed. 17a-hydroxyprogesterone derivatives 17a-ethinyltestosterone derivatives 19-nortestosterone derivatives 77 17a-hydroxyprogesterone derivatives medroxyprogesterone acetate megestrol acetate O enhanced potency and metabolic stability H H H O progesterone medroxyprogesterone Medroxyprogesterone acetate (6a-methyl-17-a-acetoxyprogesterone): Improved oral bioavailability due to suppressed metabolic hydroxylation/inactivation at C6; after oral administration rapidly deacetylated by first-pass metabolism to ‘ medroxy ’ progesterone (‘methyl-hydroxy’-progesterone). Megestrol acetate: Introduction of D6,7 enhances progestin activity. 78 17a-Ethinyltestosterone: A surprisingly active oral progestin testosterone first orally available progestin, 1938 Ethisterone (17a-ethinyltestosterone) was synthesized in an attempt to generate an orally available androgen, but it turned out to be a potent progestin. Dimethisterone was found to be more potent due to improved metabolic stability (B and D rings are shielded). 79 Potentiation of Ethisterone by 19-Demethylation: Norethisterone [= Norethindrone]=17a-Ethinyl-19-nortestosterone 19-nortestosterone testosterone 1953, Carl Djerassi OH OH H H H H H potentiation H O O Norethisterone [= norethindrone], a contraceptive progestin ethisterone 80 Progestins in Current Oral Contraceptives 19-Nortestosterone norethindrone n norethindrone n norethindrone acetate n ethynodiol diacetate n norethynodrel (1961) norgestrel Spironolactone n drospirenone n levonorgestrel n norgestrel n desogestrel n norgestimate Combination oral contraceptives include an estrogen (mostly EE, also mestranol) and one of eight available progestins. Estrogen and progestin act synergistically to inhibit ovulation, impair sperm motility, and prevent fertilization. The newer progestins are highly selective and are optimized for metabolic stability and receptor activity profile. 81 Drospirenone: Progestin of the spironolactone group ‘spiro’: denoting a molecule with two rings with one atom common to both. Spironolactone, a potassiumsparing diuretics drosperinone, a progestin - It is an analog of the potassium-sparing diuretic spironolactone. - used in birth control pills and postmenopausal hormone replacement therapy - combined oral contraceptive in a dosage containing drospirenone 3 mg/ ethinylestradiol 30 µg; In the United States, also marketed in a formulation containing folate. 82 Marketed drugs containing spirocyclic scaffolds buspirone spironolactone griseofluvine drospirenone fluspirilene Zheng et al., Bioorganic & Medicinal Chemistry Letters, Volume 24, 2014, 3673–3682 83 cevimeline exam question The two molecules shown above are synthetic progestins. Select the chemical term that best specifies the relationship between these two molecules: A. B. C. D. E. Epimers Diasteromers Oligomers Enantiomers Rotamers 84 exam question O H H H 1 O 2 OH H H O H 3 4 5 Among the progestin drugs shown above select the one displaying a spiro-cyclic structure: A. B. C. D. E. 85 1 2 3 4 5 Drospirenone: A spironolactone progestin Antimineralocorticoid effect of drospirenone. Drospirenone binds to aldosterone receptors and blocks aldosterone binding in the kidney. - Anti-androgenic effect of drospirenone. Binds to androgen receptors and competes with testosterone binding. DRSP = Drospirenone; SHBG = Sex hormonebinding globulin; T = Testosterone. antiandrogenic; conditions due to elevated levels of testosterone in women (acne etc.) Drospirenone is an aldosterone antagonist with potassium sparing properties. In women with mild or moderate renal insufficiency, or in combination with chronic daily use of other potassium-sparing medications (ACE inhibitors, angiotensin II receptor antagonists, potassium-sparing diuretics, heparin, aldosterone antagonists, or NSAIDs), hyperkalemia should be monitored. 86 Non-oral routes for hormonal contraception 87 Birth Control Patch Ethinylestradiol (25 µg)/norelgestromin (150 µg) (brand names Ortho Evra, Evra, Xulane) is a contraceptive patch containing the estrogen ethinylestradiol and the progestin norelgestromin. As of December 2016, only the generic version is marketed in the U.S. https://www.plannedparenthood.org/learn/birth-control/birth-control-patch-ortho-evra 88 emergency contraception [RU 486] 89 90 Medicinal Chemistry of Androgens PCOL 826B-Steroid Lecture 4 [pages 1346-1381 in Foye’s MedChem] [email protected] Leydig (or interstitial) cells release androgens (19-carbon steroids). They secrete testosterone, androstenedione and dehydroepiandrosterone (DHEA), when stimulated by the pituitary hormone luteinizing hormone (LH). A histological section through testicular tissue is shown: 1. Lumen of the seminiferous tubule, 7. Leydig cells, 8. capillaries 91 Androgen activation of the androgen receptor AR: androgen receptor ARE: androgen-response element CoA: coactivator HSP70: heat shock protein 70 HSP90: heat shock protein 70 CoR: corepressor GTF: general transcription factor 92 Human Androgens aromatase 5a-reductase DHT androgens potency at AR: DHT > T 93 T estrogens Testosterone-mediated physiological effects 94 Exam question Testosterone is the biological precursor of dihydrotestosterone. Among the following select the enzyme that transforms testosterone into dihydrotestosterone: A. estrogen sulfotransferase. B. CYP2D6. C. aromatase. D. 17-methyltransferase. E. 5a-reductase. 95 Inhibition of 5-DHT Biosynthesis: 5a-reductase as drug target in benign prostatic hyperplasia ‘azasteroid-7-amides’ Finasteride and dutasteride are mechanism-based inhibitors (suicide inhibitors) acting by irreversible and covalent target adduction/inactivation. Finasteride: type II 5a-reductase specific; strong suppression of prostatic and circulating DHT; (elimination half-life = 5 hours). Dutasteride: non-selective type I and II-reductase inhibitor; more efficient suppression of circulating DHT; (elimination half-life > 5 weeks). Used for treatment of BPH; [also used for male pattern baldness (androgenetic alopecia)]. 96 Finasteride: A mechanism-based inhibitor of 5a-reductase 97 Exam question Finasteride (structure as shown above) is a 5α-reductase inhibitor. Among the following terms select the one that best describes the mechanism of action of this drug: A. Allosteric modulator. B. Potentiated ligand. C. Competitive antagonist. D. Mechanism-based inhibitor. E. Channel blocker. 98