Steroid Hormones Part Two

Steroid Hormones Part Two Medicinal Chemistry III / 4th stage/ 1st Semester Lecture 9 Dr.Narmin Hama Amin Androgens Endogenous Androgens Testosterone and its more potent reduction product 5α-DHT are produced in significantly greater amounts in males than in females, but females also produce low amounts of these “male” sex hormones. Endogenous compounds have two important activities: ➢ Androgenic activity (promoting male sex characteristics) ➢ Anabolic activity (muscle building). ➢ Biosynthesis Testosterone can be synthesized through pregnenolone, DHEA(dehydroepiandrosterone) , and androstenedione Metabolism of Androgens ▪ Testosterone is rapidly converted to 5α-DHT in many tissues by the action of 5α-reductase. Depending on the tissue, this is either to activate testosterone to the more potent androgen, DHT (e.g., in the prostate), or a step in the metabolic inactivation of this androgen. The primary route for metabolic inactivation of testosterone and DHT is oxidation to the 17-one. The 3-one group is also reduced to the 3α- (major) and 3α- ols (minor). ▪ Androsterone is the major urinary metabolite and was the first “androgenic” steroid isolated. These metabolites are excreted mainly as the corresponding glucuronides Metabolism of Androgens SARs Of Androgens Testosterone exerts its physiological activity after its conversion to Dihydrotestosterone. A steroidal skeleton is minimum structural requirement to have androgenic activity. 17β hydroxyl function to be essential for androgenic and anabolic activity. Reduction of the A ring e.g., DHT may increase potency. Introduction of 17α methyl group confers oral activity on testosterone. Testosterone not effective orally, because metabolic changes at 17-β oxygen, which is used to attach the receptor site. 17-α alkyl groups prevent these metabolic changes so that compounds are orally active. E.g.17α methyl testosterone. Increasing the length of alkyl side chain at 17α position results reduced activity. Esterification of testosterone at C-17 with a number of acids have long duration of action when used parenterally. Testosterone -OH group in 17α position decreases androgenic or anabolic activity. Heterocyclic rings are also incorporated yield good anabolic agents. E.g. Stanozolol Several heterocyclic rings were then fused to ring A. the pyrazole and isoxazole were much more active then 17α-methyl testosterone. Androgenic &Anabolic Steroid Products ➢ Testosterone, USP. Testosterone, 17β-hydroxyandrost4-en-3-one, is a naturally occurring androgen in men. In women, it mainly serves as a biosynthetic precursor to estradiol but also has other hormonal effects. It is rapidly metabolized to relatively inactive 17-ones however, preventing significant oral activity. Testosterone is available in a transdermal delivery system (patch), a gel formulation, a buccal system, and as implantable pellets. Testosterone 17βesters are available in long-acting IM depot preparations ➢ Methyltestosterone, USP. Methyltestosterone, 17βhydroxy-17-methylandrost-4-en-3-one, is only about half as active as testosterone (intramuscularly), but it has the great advantage of being orally active. ➢ Oxymetholone Oxymetholone, 17β-hydroxy-2(hydroxymethylene) 17-methylandrostan-3-one, is approved for the treatment of various anemia. ➢ Oxandrolone Oxandrolone, 17β-hydroxy-17methyl-2-oxaandrostan-3-one, is approved to aid in the promotion of weight gain after weight loss following surgery, chronic infections, or severe trauma and to offset protein catabolism associated with long-term corticosteroid use. Oxandrolone is also used to relieve bone pain accompanying osteoporosis. It has been used to treat alcoholic hepatitis and HIV wasting syndrome. Structural Classes: Anabolic Androgenic Steroids Danazol and Endometriosis ➢ Danazol, USP. Danazol, , is a weak androgen that, in spite of the 17α-ethinyl group, has little estrogenic or progestogenic activity. Danazol has been called a synthetic steroid with diverse biological effects. Danazol binds to sex hormone–binding globulin (SHBG) and decreases the hepatic synthesis of this estradiol and testosterone carrier. Free testosterone thus increases. Danazol inhibits FSH and LH production by the hypothalamus and pituitary. It binds to PRs, GRs,ARs, and ERs. Although the exact mechanism of action is unclear, danazol alters endometrial tissue so that it becomes inactive and atrophic, which allows danazol to be an effective treatment for endometriosis. Danazol is also used to treat hereditary angioedema and fibrocystic breast disease Antiandrogens ▪ Antiandrogens are of therapeutic use in treating conditions of hyperandrogenism (e.g., hirsutism, polycystic overy, acute acne, and premature baldness) or androgen-stimulated cancers (e.g., prostatic carcinoma). ➢ Flutamide, Bicalutamide, And Nilutamide ▪ Three nonsteroidal antiandrogens are in clinical use in the United States— flutamide, bicalutamide, and nilutamide ▪ They are mainly used in the management of prostate cancer. ➢ Flutamide was the first of these compounds approved for use by the FDA, but liver toxicity and thricedaily dosing offered room for improvement. It was also determined that a metabolite of flutamide, hydroxyflutamide, had greater antiandrogen action than the parent. ➢ Bicalutamide, which has greater potency than flutamide, incorporates an OH into its structure at the same relative position as in hydroxyflutamide. Bicalutamide is dosed once a day and has less toxicity than flutamide and nilutamide, making it a preferred choice when initiating therapy. ➢ Nilutamide • Nilutamide, is used in combination with surgical castration for the treatment of metastatic prostate cancer. • Nilutamide, which has an elimination half-life of approximately 40 hours, can also be used in once-daily dosing, but it has side effects that limit its use—visual disturbances, alcohol intolerance, and allergic pneumonitis. Inhibition of 5α-Reductase 5α-DHT is important for maintaining prostate function in men. DHT also plays a major role in the pathogenesis of benign prostatic hyperplasia (BPH). Finasteride, is a potent, slow, tight-binding inhibitor of 5α-reductase that functions by a unique mechanism. Finasteride is a relatively selective inhibitor of type II 5α-reductase. This enzyme is present in high levels in the prostate and at lower levels in other tissues. Because of the strong connection to the formation of DHT in the prostate, it was theorized that specific inhibition of this isoform would yield the greatest therapeutic effect. A second use of finasteride is in the treatment of male pattern baldness. The conversion of testosterone to DHT in advancing years leads to thinning of hair in men. Inhibition of this conversion was envisioned as a possible baldness treatment. ➢ Dutasteride, a newer drug for treating BPH, inhibits both isoforms of the enzyme . ➢ Dutasteride bears an aromatic amide at C17, rather than the t-butyl amide seen in finasteride. Both drugs are effective at treating BPH, but a recent retrospective study suggests that rates of acute urinary retention are lower with dutasteride. Adrenal cortex hormones Corticosteroids (typically made in the adrenal cortex) a) Glucocorticoids such as cortisol b) Mineralocorticoids such as aldosterone ➢ Endogenous Corticosteroids: The adrenal glands (which lie just above the kidneys) secrete over 50 different steroids, including precursors for other steroid hormones. The most important hormonal steroids produced by the adrenal cortex, however, are aldosterone and hydrocortisone. Aldosterone is the primary MC in humans (i.e., it causes significant salt retention). Hydrocortisone is the primary GC in humans (i.e., it has its primary effects on intermediary metabolism). The GCs have become very important in modern medicine, especially for their anti-inflammatory effects. Aldosterone and, to a lesser extent, other MCs maintain a constant electrolyte balance and blood volume. The GCs have key roles in controlling carbohydrate, protein, and lipid metabolism. Aldosterone increases sodium reabsorption in the kidneys. An increase in plasma sodium concentration, in turn, will lead to increased blood volume, because blood volume and urinary excretion of water are directly related to the plasma sodium concentration. Simultaneously, aldosterone increases potassium ion excretion. The GCs have many physiological and pharmacological actions. They control or influence carbohydrate, protein, lipid, and purine metabolism. They also affect the cardiovascular and nervous systems and skeletal muscle. GCs stimulate glycogen storage synthesis by inducing the synthesis of glycogen synthase and stimulate gluconeogenesis in the liver. They have a catabolic effect on muscle tissue, stimulating the formation and transamination of amino acids into glucose precursors in the liver Biosynthesis of Aldosterone and hydrocorticone Therapeutic Uses of Adrenal Cortex Hormones ▪ The adrenocortical steroids are used primarily for their GC effects, including immunosuppression, anti-inflammatory activity, and antiallergic activity. ▪ The MCs are used only for treatment of Addison disease. Addison disease is caused by chronic adrenocortical insufficiency and may be due to either adrenal or anterior pituitary failure SARs of Glucocorticoids Systemic Corticosteroids 1- Mineralocorticoids ( high salt retention ) ➢ Fludrocortisone: The 9a-ﬂuoro analog (ﬂudrocortisone) is approximately 11-fold as potent as cortisone acetate Fludrocortisone is orally administered as its 21-acetate derivative.

Load more