Med Chem II exam 3 - Dr. Mehanna PDF

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MedChem II – Exam 3 Drugs Hormones 1. Steroidal Hormones - Corticosteroids - Sex Hormones 2. Thyroid Hormones 1. Steroidal Hormones Backbone: Steroidal Nucleus = 17 carbons with 4 rings The further substitution on the steroidal nucleus will give us a new name for the parent nucleus which relates to the hormone that relates to the nucleus Additional methyl @ C13 à #18 à takes nucleus called Estrane - Estrogens have this Estane backbone Additional methyl to Estrane @ C10 à #19 à Androstane - Testosterone have this Androstane backbone Additional 2 carbons to C17 à #20 & 21 à Pregnane Cholesterol = 27 carbons = Cholestane nucleus They all have chiral centers; dotted lines are described as alpha & the solid lines are beta

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Steroidal Hormones: Corticosteroids (21 carbons) all have carbonyl at C-3 double bond between C-4 &5 substitution at C-11 carbonyl at 20 hydroxy group at C-21 nucleus: pregnane

Corticosteroids are synthesized from adrenal cortex - Outer: produces mineralocorticoids - Intermediate: produces glucocorticoids - Inner: produces androgens Mineralocorticoids - Used to regulate/enhance Na reabsorption or else, you keep losing Na; your urine w/ no control à hypotension - If there are excessive mineralocorticoids, it causes edema—water retention à hypertension - Used for Addison’s Disease: deficiency in mineralocorticoids Name “mineralo” = minerals =sodium Aldosterone - Hydroxyl (C-11) Structure - Aldehyde (C-18) à oxidation à hemi-acetal - Carbonyl (C-20) - Hydroxyl (C-21) MOA - Aldosterone regulates exchange at distal tubule - Retains excessive sodium à moon face edema - Responsible for maintaining BP by reabsorption of Na - Wherever sodium goes, water goes à increase pressure Enhances Na reabsorption; acts against diuresis Effect Activity - 200: 1; Mostly mineralocorticoid activity (mineral:gluco) Therapeutic - Addison’s disease (adrenal insufficiency) à as replacement therapy use Other Any structure with aldehyde at C-18 = mineralocorticoid

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Glucocorticoids Regulate your blood glucose levels; every morning the glucocorticoids are released to break down glycogen into glucose and make you ready for energy - stimulate the biosynthesis of glucose from AA (gluconeogenesis) *** - stimulate the breakdown of glycogen into glucose Therapeutic uses: - Anti-inflammatory for rheumatoid arthritis & boosts immune system - Asthma - Skin diseases for psoriasis, eczema, allergic reactions “gluco” = glucose Name Hydrocortisone Structure - Same structure as aldosterone with a few additions: - Methyl (C-18) - Alpha hydroxyl (C-17)—oxidation

MOA

Cortisone

Effect Activity (mineral:gluco) Therapeutic Use

Other

Structure

Modification from hydrocortisone: - Alpha fluoro (F) at C-9 à alpha-9 fluoro

Activity (mineral:gluco)

800:10; much more mineralocorticoid activity

Fludrocortisone

Therapeutic Use

Other

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- Ketone (C-11) for Cortisone Increase glucose concentration in blood Stimulate gluconeogenesis - Build-up of glucose from amino acids - Decrease inflammation - Steroidal anti-inflammatory drugs à major therapeutic use - Minimize mineralocorticoid activity & maximize glucocorticoid activity (otherwise severe hypertension) Increase glucose levels in the blood - 1:20; Mostly glucocorticoid activity - MIXED ACTION (min & glu) à problem: you don’t want mineralocorticoid, only for Addison’s disease - Psoriasis - ADR: Sodium retention, increase BP, & moon face (water retention in the face à a lot of edema) - Note: drug has non-selectivity - Asthma - Has a component of inflammation - Dermatitis: Inflammation of the skin - Oxidation at C-11 (into carbonyl) = Cortisol - Occurs in adrenal gland - Cortisol & Hydrocortisone have same activity - Increases BP & blood sugar -

If deciding between aldosterone & fludrocortisone à use fludrocortisone because of the increased activity for Addison’s Disease ADR: Sodium retention, increase BP, & moon face

Prednisolone

Glucocorticoids Modification from hydrocortisone: Structure - Add additional double bond in ring A between C-1&C-2

Activity (mineral:gluco)

Structure

Modification from hydrocortisone: - Add additional double bond in ring A - Change C-11 to ketone

Prednisone

Activity (mineral:gluco)

Triamcinolone Structure

Activity

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10:200

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ADR: Sodium retention, increase BP, & moon face

3 modifications that got rid of mineralocorticoid activity: - Add alpha fluoro at C-9 - Add double bond in ring A - Add OH at C-16 -

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Triamcinolone Acetonide

10:200 More glucocorticoid activity & minimum mineralocorticoid activity (not zero) because of the double bond

Cushing Syndrome: not enough glucocorticoids in system - Need immunosuppressive therapy ADR: Sodium retention, increase BP, & moon face

Therapeutic Use Other

Other

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Very high affinity to glucocorticoid Almost 0 mineralocorticoid activity - mineralo increases BP, we want to treat inflammation without raising BP Therapeutic use: anti-inflammatory, rheumatoid arthritis, asthma, skin diseases (eczema, psoriasis) Used orally as suspension, skin ointment & by inj (IM & IV) Polar nature à poor penetration through skin/ GIT & biomembrane - Problem: very lipophilic group prevents bioavailability

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Modify triamcinolone by removing polar group (2-OH) to increase lipophilicity/bioavailability to have better penetration through the skin, GIT or bronchial tissues - The diol and acetone form a lucosidic link àloss of 2 OH groups à triamcinolone acetonide - Water insoluble so used orally as suspension, skin ointment/cream & by IM suspension

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They make ester forms by taking 2 hydroxyl groups at C-17 & 21 and make dipropionate esters - esters = no oral use, just topical use - used as creams for skin problems - used as aerosol for inhalation to treat asthma - least ADR

Other

Dipropionate Ester

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Dexamethasone

Glucocorticoids Modification from triamcinolone: Structure - Change OH at C-16 to CH3 (alpha-16 methyl) - CH3 = bioisostere of OH that is more lipophilic Absorption More non-polar à better absorption (from skin, GIT, inhalation) Other

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Used orally, but still poor bioavailability Can make dipropionate with ester (topical only) Immediately acting: IV with ester w/phosphoric acid because phosphoric acid has 3 acidic functionalities; it has more than 1 acidic functional group - 1 of them make ester at C-21 - Other 2 make Na salts Prodrug; once injected, the ester function will hydrolyze giving you the dexamethasone at site of injection

Betamethasone

Modification from triamcinolone to increase lipophilicity - Change OH at C-16 to CH3 (beta-16 methyl) Absorption More non-polar à better absorption (from skin, GIT, inhalation) - Used orally, but still poor bioavailability - Cannot make dipropionate with ester (topical only) Other - For betamethasone, the dipropionate ester is eye drops for macular degeneration

Beclometasone (as a dipropionate ester)

Modification from betamethasone: - Change fluoro to chloro at C-9 to increase lipophilicity Absorption - Better bioavailability - Used as aerosol or nasal spray (brand: Beclovent) - Pro-drug that needs to be hydrolyzed by esterases - Used to suppress the inflammation of bronchi - They cannot be used to reverse already existing asthma. They are prophylactic for potential development of asthma. Bronchi Other inflammation is part of the asthma process, so you give this steroid to suppress the potential of bronchi inflammation, but once an attack occurs, it is ineffective. Should be on this drug continuously

Clobetasol (as a dipropionate ester)

Structure

Structure

Structure

Modification from fluocinolone: - Change one of the fluoros to chloro (at a different position) - 2 halogens à 1 fluoro, 1 chloro

Absorption Other Mometasone Furoate (with furoic acid)

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Used as creams or aerosol or nasal spray

Modification from clobetasol: - Change the fluoro to chloro - 2 halogens à 2 chloros Absorption Better bioavailability because the chloro has a bigger atom than fluoro Structure

Other -

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Better bioavailability It is more lipophilic, so you decrease the number of hydroxyl and use it as mono-ester

Used only topically for psoriasis & eczema Pro drug: rationale for all the function groups: makes it more lipophilic, better penetration through the skin, gives you the action you need Used also as nasal spray for asthma

Overview How to make the product more bioavailable -

Acetonides: Fluocinolone & Triamcinolone o React a diol (glycol) with acetone § Remove a water molecule between the two molecules = acetonide preparations (“acetonides”) o Start with triamcinolone § Modify the polarity • Take the two OH’s next to each other & react with acetone § Increase the bioavailability • Eliminate 2 lipophilic groups & add more carbons o Acetonides = reaction of diol with acetone § Pro-drug • Broken down chemically the opposite way they are formed

Acetone

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Lipophilic esters (dipropionate esters): o Take all of the OH (at least C-16 and C-17) and esterify it with propionic acid = propionate esters o Properties of esters: Propionic acid § More volatile than original produces à important for asthma preparations § More polar = better absorption § Better lipophilicity à can be used topically § Pro-drug • Broken down by esterases after being in contact with plasma o This is not a water-soluble salt, it is a depot à but these are not used IM § Only used orally, topically, or by inhalation o Note: you can’t esterify a structure with a group bigger than propionate because then it would be an oily substance and we are not using these as IM preparations

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Take acetonides + lipophilic esters and put into one structure o All have minimum mineralocorticoid affinity

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How to make a drug into an IV preparation Start with triamcinolone à currently polar but not water soluble o To be able to administer as an IV, product has to be water soluble o Take the hydroxyl & make it a sodium salt with phosphoric acid “Triamcinolone phosphate” o Ester Phosphoric acid o Water soluble § Not meant to have increased lipophilicity, meant to have water solubility § Used as a method to inject into veins because we can’t inject solids into vein o Pro-drug § Once in plasma, breaks down to the original form

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Review Modifications from hydrocortisone to increase activity at the glucocorticoid receptor: Picture

Hydrocortisone / Cortisol

Key structure Carbonyl (C-3) Double bond (C-4/C-5) Hydroxyl (C-11) Alpha hydroxyl (C-17) à dotted line Carbonyl (C-20) Hydroxyl (C-21)

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GCR activity with very high MCR activity

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Alpha-9 fluoro

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300 : 1 (MCR : GCR) X 10 GCR activity X 300 MCR activity

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Add additional double bond in ring A

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X5 GCR activity Minimum MCR activity (not zero) because of double bond

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Add additional double bond in ring A Change C-11 to carbonyl

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X5 GCR activity Minimum MCR activity (not zero) because of double bond

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Very high GCR activity No MCR activity

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Problem = very lipophilic group impedes bioavailability

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Fludrocortisone

Prednisolone

Prednisone

Triamcinolone

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Activity

Add alpha fluoro at C-9 Add double bond in ring A Add hydroxyl at C-11

Modifications from triamcinolone to increase absorption: Picture

Key structure

Triamcinolone

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Change OH at C-16 to CH3 (alpha-16 methyl)

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Change OH at C-16 to CH3 (beta-16 methyl)

Dexamethasone

Betamethasone

Bioavailability / absorption • Very high GCR activity • No MCR activity •

Problem = very lipophilic group impedes bioavailability

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More non-polar à better absorption (from skin, GIT, inhalation)

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More non-polar à better absorption (from skin, GIT, inhalation)

Modifications from previous structure to increase absorption (by modifying halogens): Picture

Key structure •

Change OH at C-16 to CH3 (beta-16 methyl)

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More non-polar à better absorption (from skin, GIT, inhalation)

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Change fluoro to chloro at C-9

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Better absorption because there is a bigger atom

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Add another halogen (fluoro) F makes it an oil: rubbing oil for eczema or psoriasis

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Better absorption because there are two halogens

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Better absorption because chloro is a bigger atom (halogen) than fluoro

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Better absorption because there are two chloros (bigger atoms than fluoro)

Betamethasone

Beclometasone

Fluocinolone

Absorption

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Clobetasol

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Change one fluoro to chloro

Mometasone

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Change the other fluoro to chloro

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Steroidal Hormones: Sex Hormones Female Sex Hormones: - Pregnane nucleus (21 carbons) - Corticosteroids - Progesterone - Estrane nucleus (18 carbons) - Estradiol (one female sex hormone) Male Sex Hormones: - Androstane nucleus (19 carbons) - Testosterone HP Axis All female sex hormones = under control of the HP axis Hypothalamus à pituitary gland à ovaries (organ) - Hypothalamus releases FSH or LH releasing factor (peptide) - Pituitary gland releases LH and FSH - Ovaries produce & release estradiol and progesterone Negative feedback inhibition - Once estradiol or progesterone levels raise too much à shuts off release of FSH or LH - MOA of contraceptives Reproductive process: - Estradiol = high in first half - Progesterone = high in second half Fertilization Estrogen produces ova from follicles Progesterone - Prepares uterus for fertilizing the ova (increases luteinizing effects à luteinizing phase) - Uterus swells à a lot of blood supply - If ova is fertilized it can implant into uterus wall - Important for maintaining pregnancy - Sheds uterus wall if women is not pregnant à menstruation Female sex hormones • Function

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Therapeutic use

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Estrogen Promote puberty (important for sex changes) Promote conversion of follicles into ova (released in uterus) Increases bone growth Hormonal replacement therapy (especially for women with menopause) Osteoporosis Contraceptive Anti-cancer agent for male prostate cancer

Progestin • •

Helps maintain pregnancy Sheds uterine wall (menstruation)

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In-vitro fertilization Habitual abortion (miscarriage) Contraceptive o Blocks feedback that causes release of LH

Males and females produce both estrogens and progestins but in different percentages

Estrogen Structure: - Parent nucleus = estrane (18 carbons) - Ring A is always aromatic (unique to estrogens) - If ring A is not aromatic, structure has no estrogen functionality - The more double bonds in ring A, the more a chair formation deviates from being a chair - Three double bonds = flat structure (no chair) - Drives molecule to specific receptors à estrogenic receptors look for aromatic ring A Natural Estrogens: produced by ovaries Estrace Brand Estradiol Structure - 2 hydroxy groups (C-3, C-17) - Phenol at C-3 & C-7 Absorption Metabolism These hormones are interchangeable in the system: Estradiol à oxidation (C17) à estrone Estrone à hydroxylation à estriol System can terminate biological activity of estrogen by making structure more polar à undergoes phase 2 metabolism All three are active but estradiol has highest activity while estriol has least

Estrone

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High oral absorption à 17 carbon steroid Extensive first pass metabolism - Oxidation into estrone (much less active) - Phase 2 metabolism at C-3 or C-17 - Each hydroxyl can form phase 2 conjugates - Undergoes sulfuration à act with sulfate & form sulfate conjugates - Very polar à goes straight to the urine - Given orally for all of the therapeutic uses - Very poor bioavailability due to first pass metabolism - Bioavailability depends on lipophilicity related to absorption or first pass metabolism CYP takes the 2 hydrogens, oxidation into ketone Secondary alcohol needed for metabolism

Dose

You only need small amounts (mcg) to activate the estrogen receptors, but to offset the quick oxidation, these are given in high MG

Other

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Brand Structure

Given as vaginal cream to bypass metabolism or transdermal patch

Theelin - Ketone (C-17) - It is not possible to have a ketone at C-3

Other

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Considerably less active than estradiol, but still active We don’t use it because it is already oxidized into ketone at c-17 & undergoes hydroxylation into estriol quickly à doesn’t solve problem

Structure

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3 hydroxy groups (C-3, C-16, C-17) “Triol” Final metaboliteàInactive Quickly excreted Oxidation by additional hydroxyl at C-16 process is very fast, so you have bad oral bioavailability

Estriol Other

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Natural Estrogens Pharmaceutical Dose dorms to bypass metabolism: - To make more fatty acid for ester as IM, add cypionate & valerate (not salts, ESTERS) - They are designed for IM when in this formulation, not oral because more lipophilic, but not absorbed, for better bioavailability - Designed for IM, depot in the muscle (all are oils) release for longer period of time & this skips the liver Brand

Depo-estradiol

Estradiol cypionate Structure

Key structure: long fatty acid ester - Estradiol cypionate = cyclopentyl propionic acid IM depot injection (no solubilizing functional group for IV) - Make C-17 into fatty acid ester à product = rich in carbons (oily) - Solubilized in muscle because muscle = protein & product = lipophilic - Product released into plasma over 2 – 3 weeks - Not a salt à it is a long acting IM ester

Metabolism Broken down by esterases into estradiol—Pro-drugs Estradiol Valerate (Delestrogen)

Use

Other

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Hot flashes (post-menopausal women), hormone replacement therapy, contraceptive Benefits: - Doesn’t go to liver à prevents first pass metabolism - Released over period of time à no multiple dosing

Semi-synthetic estrogens: altered natural estrogen -

All given orally à required modification in structure to prevent first pass metabolism - Oxidation at C-17 into ketone = less active hormone à excreted via phase 2 - Primary, secondary, tertiary alcohols à oxidation: 1⁰: oxidation à formaldehyde à formic acid 2⁰ (isopropanone): oxidation à acetone - Remove O from the O and adjacent C 3⁰: adjacent carbon to the hydroxyl doesn’t have a OH so it cannot be oxidized - Will resist metabolism which is desired with estrogens - Hydroxyl (C-17) normally secondary in estradiol - Make into tertiary alcohol by adding R group onto C-17 to prevent...