I.FF.MC LECTURE ppt 15.ppt

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    STEROID HORMONES: ADRENOCORTICOIDS

    (ADRENAL STEROIDS)

    The adrenal gland is a cap-likeorgan sitting at the upper pole of the

    kidney. Histologically, the gland consists of the inner adrenal

    medulla and the outer adrenal cortex (shell). In accord with thishistological differentiation, there are two endocrine organs within

    the adrenal gland, one surrounding the other. The inner adrenal

    medulla secretes the catecholamines: epinephrine and

    norepinephrine. The outer adrenal cortex secretes corticosteroid

    hormones: glucocorticoidsand mineralocorticoids.

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    The adrenal cortex is divided into three zones:

    zona glomerulos a (ou ter),

    zona fasc icu lata (m idd le), and

    zona reticu lar is (inner).

    Al th ough these three zones are var iable in their anatom ical

    distinctness, they are definite in their biochemical

    distinctness. All three cortical zones secrete corticosterone:

    the zona glomerulosa biosynthesizes aldosterone; the zona

    fasciculate and zona reticularis biosynthesize cortisol (and

    sex hormonesas well).

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    Like most endocrine glands, the adrenal cortex is regulated by

    hypothalamo-pituitary peptides. The hypothalamus secretes

    co rt icotrop in releasing factor (CRF), which controls the release of

    adrenocort ico tropin (ACTH), a peptide cons ist ing of 39 amino

    acids. Corticotropin secretion is under feedback regulation by the

    adrenal steroids, as well as being under the control of higher CNS

    centers; stress or epinephrine can also increase corticosteroidproduction. Adrenocortical secretion is controlled primarily by

    ACTH from the anterior pituitary, but mineralocorticoid secretion

    is also subject to independent control by circulating factors, of

    which the most important is angiotensin II.

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    On the basis of biochemical effects, the two groups of

    corticosteroids can be readily distinguished:

    1. Glucocorticoids, which act on carbohydrate, fat,and pro teinmetabol ism

    2. Mineralocorticoids, which regulate electrolyte

    balance through Na+retent ion

    Since these two classes of corticosteroids are bothimportant in medicinal chemistry and drug design,

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    Glucocorticoid Receptor

    The glucocorticoid receptor protein belongs to a superfamily of nuclear

    receptor proteins that includes steroid, Vitamin D, thyroid, retinoic acid, and

    other receptors that interact with promoters that regulate the transcription of

    target genes. Although the glucocorticoid receptor differs from the estrogenor progesterone receptors, the basic principles of its action seem to be the

    same. The glucocorticoid receptor is 800 amino acids in length and has three

    functional domains: the C-terminal has the glucocorticoid binding region, the

    middle portion has the DNA binding region (containing nine cysteine residues

    folded into a two finger structure stabilized by Zn2+ ions), and the N-

    terminal, which has the receptor-specific region. A gene for the classicglucocorticoid receptor has been identified. Binding to the glucocorticoid

    receptor is somewhatdependent on temperature, being optimal at 37C.

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    Glucocorticoids: StructureActivity Correlations

    The structureactivity relationships of glucocorticoids are based on two

    natural hormones, cortisol (15.1) and corticosterone (15.2). The

    characteristic structural features of these hormones are the conjugated 3-ketone, the 11-OH group, and the l7 beta-ketol side chain. Molecular

    modifications have been aimed at deriving compounds with glucocorticoid

    (and anti-inflammatory) actions but lacking in mineralocorticoid effects and

    side effects. Substituents added to the cortisol molecule may alter

    bioactivity and receptor binding affinity independently of other functional

    groups present on the molecule.

    Cortisol (15.1)O

    OH

    H

    H

    H

    OHHO

    O

    Corticosteron (15.2)O

    H

    H

    H

    OHHO

    O

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    1. Halogenation. 9 lfa-Fluorocortisone is only about 10 times more active

    than its parent compound, but its mineralocorticoid activity is 300600 times

    greater. This is undesirable since it leads to edema; thus, the compound

    fludrocortisone (15.3) is used only topically, in ointments.2. Additional double bonds. 1-compounds (where .1 indicates the position of a

    double bond) were introduced, like prednisone (15.4), a .1-11-ketone, and

    prednisolone, its 11-hydroxy analogue. Changing the geometry of the A ring

    increased the potency without augmenting mineralocorticoid activity.

    Fluorocortison (15.3)O

    OH

    H

    H

    F

    OHHO

    O

    Prednison (15.4)O

    OH

    H

    H

    H

    OHO

    O

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    The introduction of a methyl group in methylprednisolone (15.5) resulted

    in a slight increase in activity; however, the greatest improvements in

    activity came from the combination of a double bond, halogen, and

    methyl substituents. Triamcinolone (15.6),in the form of its acetomide (an

    acetone ketal), shows a 9-fluoro group in addition to .1 unsaturation,

    and a 16-OH. It is used in treating psoriasis and other dermatological

    problems.

    Methylprednison (15.5)

    O

    OH

    H

    H

    H

    OHHO

    O

    Triamcinolon (15.6)

    O

    OH

    H

    H

    F

    OHHO

    O

    OH

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    Dexamethasone (15.7), perhaps the most active and highly stable

    glucocorticoid, is the 16lfa-methyl analog of triamcinolone. It is interesting to

    note that progesterone binds well to the glucocorticoid receptor despite a

    missing 11-oxygen functional group, but it fails to elicit gene activation inglucocorticoid target cells, thus shedding light on the role of the 11-OH group.

    The optimum glucocorticoid structure shows a 1lfa, 2bet-half-chair

    conformation for ring A, with ring D as a 13-envelope (C-13 is bent up) or a

    half-chair. Halogenation is most effective in positions 6, 7, 9, and 12. The

    compounds bind on their face by hydrophobic binding forces.

    Dexamethason (15.7)O

    OH

    H

    H

    H

    OHHO

    O

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    5.12.3 Glucocorticoids: Pharmacological Activity

    The most important clinical application of glucocorticoids and their semisynthetic

    analogs is their anti-inflammatory activity, discovered in 1949 by Hench and co-

    workers. The profound anti-inflammatory effects of glucocorticoids arise from the

    combined effects of these steroids on both the cellular and molecular mediators

    of inflammation; these effects are separate from the metabolic effects described

    above and further indication of the widespread diversity of macromolecules to

    which steroids can bind. Glucocorticoids suppress inflammation at the cellular

    level by downregulating the concentration, distribution, and function of

    leukocytes (white blood cells) that profoundly influence inflammation and

    response to infection within the body (In this way, steroids help to mediate the

    overlap between the endocrine systems [chapter 5] and the immune systems

    [chapter 6]). Glucocorticoids also suppress inflammation at the molecule level by

    suppressing inflammatory cytokines, chemokines, and other molecular mediatorsof inflammation.

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    Glucocorticoids: Inflammation versus Infection

    The use of anti-inflammatory steroids also demands an appreciation

    of the differences between the processes of infection and

    inflammation. An infection is a pathological process whereby an

    exogenous agent (fungus, bacterium, virus, prion) invades the body,

    either locally or systemically, causing some form of injurious

    dysfunction. Inflammation, on the other hand, is the bodysphysiological endogenous response to an injury, be it caused by an

    infective agent or some other process (trauma, chemical). Although

    inflammation is a normal physiological response, it may become

    pathological under certain circumstances; for example, inflammation

    of the bronchi in the lungs due to inhalation of a toxic chemical maycause so much swelling in the bronchial lining that the flow of air into

    the lung is blocked, resulting in a pathological state.

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    Infections are usually accompanied by inflammation. The reddenedarea around a skin abscess reflects the bodysinflammatory response

    to the infection. If one puts topical steroids on such an infection, the

    redness disappears, reflecting suppression of the inflammation and

    giving the erroneous impression that the infection has been

    successfully treated; in truth, the infection is now spreading much moreaggressively since the bodysinflammatory defense system has been

    suppressed. Nevertheless, sometimes it is necessary to cautiously use

    anti-inflammatory steroids in the presence of an infection. For

    example, pneumonia may be associated with a dangerous

    inflammation of the airways, causing decreased air entry into the

    lungs. Under such circumstances, the combined use of an anti-inflammatory steroid with the appropriate antibiotic is justified.

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    STEROID HORMONES:

    ADRENOCORTICOIDSMINERALOCORTICOIDS

    Mineralocorticoids such as the natural hormone aldosterone (5.66)

    regulate electrolyte concentration by stimulating Na+retention in kidney

    cells. 11-Desoxycorticosterone (5.67) and fludrocortisone (5.62) are

    much less active, but are used for maintaining electrolyte balance in

    adrenal insufficiency. Aldosterone synthesis is probably regulated by

    ACTH and angiotensin, a peptide hormone. This hormone has its own

    receptors in kidney cells. Hyperaldosteronism can play a role in highblood pressure.

    Aldosterone (15.8)O

    H

    H

    H

    OHHO

    O

    O

    11-Deoxycorticosteron (15.9)O

    H

    H

    H

    OH

    O

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    Spironolacton (15.10)

    OH

    H

    H

    O

    O

    SO

    Aldosterone antagonists such as spironolactone (15.10) are

    therefore useful as hypotensive diuretic agents, because the

    increase in Na+excretion that they promote is always paralleled by

    an increased urine volume.

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    Structurally, aldosterone differs from glucocorticoids in having an 18-

    aldehyde group and lacking the 17-OH. The aldehyde participates in

    a tautomeric equilibrium, forming a cyclic hemiacetal ring.

    Spironolactone, a synthetic compound and antiandrogen, has a

    lactone ring attached to C-17 through one common carbon (a spiro

    compound) and the 7-thiolester group. The structure of themineralocorticoid receptor has been deduced through cloning of its

    cDNA. It shows considerable structural and functional similarity to the

    glucocorticoid receptor.

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    The most important pharmacological action of glucor t ico ids

    and their semisynthetic analogues is their

    a. antiinflammatory

    b. and antirheumatic activity, discovered in 1949 byHench and co-workers.

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    Relative glucocorticoid and mineralocorticoid activity of some corticoid

    derivatives

    Relative glucocorticoid

    potency

    Relative meneralocorticoid

    activity

    Cortisol 1 1

    Fluorocortison 10 300Prednison 3 0,8

    Methylprednisolone 5 0

    Triamcinolone 6 0

    Dexamethason 30 0

    11-deoxycorticosterone 0 30Aldosteron 0,2 600

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    Although the mode of action of glucocorticoids is unknown,

    there are certain indications that:

    a. they interfere with prostaglandin and collagenase

    synthesis,

    b. and the circulatory distribution of leukocytes in

    inflamed tissue,c. as well as inhibiting edema by decreasing capillary

    permeablity.

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    These steroids are also effective:

    a. in some allergic diseases, such as

    bronchial asthmab. and in urticaria

    c. and other types of dermatitis.

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    LIPIDS AS DRUGS AND DRUG DESIGN TARGETS

    In 1934, von Euler in Sweden discovered a group of polyunsaturatedfatty acids that had a powerful effect on smooth muscle and blood

    pressure. They were isolated from seminal fluid and the prostate, and

    were named prostaglandins. Their structure was elucidated by the

    Samuelsson group in Stockholm, who, in 1975, also discovered even

    more potent fatty acid metabolites, the thromboxanesandprostacyclin.The effect of these compounds on blood platelet aggregation and the

    contraction of blood vessels connected them to the etiology of stroke

    and cardiovascular disease. Additionally, it was discovered that both

    steroidal and nonsteroidal anti-inflammatory agents act through the

    prostaglandin system, adding further impetus to the research in this

    area. Consequently, the field of bioactive lipids became a center of

    intense interest.

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    As the research area expanded, the leukotrienes were

    discovered next. The leukotrienesare potent lipid mediators

    associated with asthma and allergic reactions. In contrast

    to prostaglandins, leukotrienes are made predominantly in

    inflammatory cells, like leukocytes, macrophages, and mast

    cells. Prostaglandins, thromboxane, and the leukotrienesare lipids that are collectively called eicosanoids, since they

    are all derived from the C20 fatty acid, arachidonic acid

    [eicosa (Gr.) = twenty]. Over the past twenty years, the

    eicosanoids have emerged as important molecules aroundwhich to target drug design and development.

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    Prostaglandins A, PGB, PGC are inactive degradation products.

    O

    PGA

    O

    PGB

    O

    PGC

    OH

    PGD

    O

    O

    PGE

    HO

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    Pharmacological effects of prostaglandins and thromboxane

    Blood vessels Bronchi

    Protaglandin E2 Dilatation Dilatation Oxytocic

    Prostagcyclin ( PGI2) Dilatation Agregation ihb

    Prostaglandin E2 Contriction Contriction Oxytocic

    Thromboxane (TXA2) Contriction Agregation

    Compouns Platelet Uterus

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    Prostaglandins, prostacyclin, and thromboxane are

    considered local hormones or autocoid,

    synthesized in many different organs and acting

    locally. They are not stored like neurotransmitters

    or conventional hormones, but are continuously

    synthesized and released immediately into the

    circulation, where they are usually deactivated after

    only one passage through the lungs. The synthesis

    depends on the availability of the starting material,arachidonic acid, and is modulated by c AMP.

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    3. The oxytocic activity of prostaglandin is used

    clinically. Prostaglandin E2 can indude labor at term

    in pregnant women, while PGF2 and its ester is

    probably due to a direct effect on uterine muscle.

    4. Other effects of the prostaglandins includebronchodi la t ionby the PGE series and constriction

    by PGF2, as well as anti-ulcer and antisecretory

    effects of some synthetic analogues in the stomach.

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    The fol low ing effects of pros tagland ins

    1. Vasodilation and constriction: PGE2 and especially PGI2

    (prostagcyclin) are powerful, short-acting vasodilators,

    probably involved in blood-pressure regulation.

    Prostaglandin F2 and TXA2. on the other hand, are potent

    vasoconstrictors.2. Blood-phlatelet aggregation is an all-important mechanism

    in normal blood-clot (thrombus ) formation, and therefore

    also highly significant in the pathophysiology of

    cardiovascular disease, stroke, coronary occlusion, and

    other circulatory catastrophes.

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    E. Ant i in f lammatory Agents and Minor Analges ic

    An ti inf lamm atory agentsare believed to act by distrupting the

    arachidonic-acid cascade. These drugs are widely used for the

    treatment of minor pain and also for the management of

    edema and the tissue damage resulting from arthritis.

    The adrenal steroids (corticosteroids) probably act by

    blocking phospholipase A2. the enzyme that liberates

    arachidonic acid from phospholipids. These steroid also

    inhibit collagenase, an enzyme responsible for damage to the

    cartilaginous tissue in joints affected by arthritic diseases.

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    8.5.1 Prostaglandins and Thromboxanes

    8.5.1.1 Prostaglandins: Structure and Bios ynthesisThe biosynthesis of prostaglandins and thromboxanes starts from

    arachidonic acid. Arachidonic acid, obtained from its phospholipid

    form by the action of phospholipase A, is cyclized to prostaglandin

    endoperoxide (15.11) in the form of PGG (a side-chain peroxide), fromwhich PGH2 (a side-chain hydroxyl) is obtained. Interleukin-1, a

    cytokine produced by leukocytes and possessing multiple

    immunological roles, mediates inflammation by increasing

    phospholipase activity and thus prostaglandin synthesis. The first

    reaction in prostaglandin biosynthesis is catalyzed by PG

    cyclooxygenase in the presence of O2 and heme. The second

    reaction requires tryptophan, probably as a source of electrons.

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    CO2HO

    O

    Prostaglandine Endoperoxide (15.11)

    OH

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    Structure of prostaglandin and thromboxanes

    CO2H

    O

    HO

    OHPGE1

    CO2H

    O

    HO

    OHPGE2

    1247

    10

    13

    20

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    CO2H

    Arachidonic acid

    Phospholipase

    Phospholipid

    C

    Phospholipid-esterified

    arachidonic acid

    OCH

    CH2OCO(CH 2)nCH3

    CH2OPOR

    O

    O

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    CO2H

    Arachidonic acid

    Phospholipase

    Phospholipid

    Corticosteroids

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    The non steroidal ant i inf lammatory agentsblock the cyclooxygenase

    that converts arachidonic acid to PGG2 and PGH2. Since the cyclic

    endoperoxidides are the prcursors of all prostaglandins, the synthesis

    of the latter is interupted.

    CO2H

    Arachidonic acid(AA)

    CO2HO

    O

    Non steroidal antiinflammatory agentsAA cyclooxygenase

    2 O2

    Prostaglandin endoperoxida

    O[O]H

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    Leukotr ienes,- which have been called slow-

    reacting substance (SRS) -are compounds

    intimately involved in anaphylactic reaction, allergic

    reactions, and asthma. Like the prostaglandins,

    thye are lipids, formed from arachidonic acid by

    lipoxygenase and glutathione. Their structure and

    biosynthesis were also elucidated by the

    Samuelsson group (Samuelsson, 1980), and are

    shown in Fiq.

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    CO2H

    CO2H

    OOHH

    C5H11

    OCO2H

    Arachidonic acid(AA)

    Lipoxygenase

    5-HPETE

    Leukotriene A (LTA)

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    Anti-Prostaglandins as Anti-InflammatoryAgents and Minor Analgesics

    Anti-inflammatory agents are believed to act by disrupting the

    arachidonic acid cascade. These drugs are widely used for the

    treatment of minor pain and arthritis. Some of them are antipyretics(drugs that reduce fever) in addition to having analgesic and

    antiinflammatory actions. Some of these agents are widely available in

    over-the-counter (OTC) preparations. Collectively, these are referred to

    as nonsteroidal anti-inflammatory drugs (NSAIDs). They may be

    classified as follows:

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    The nonsteroidal anti-inflammatory agents block the

    cyclooxygenase enzyme that catalyzes the

    conversion of arachidonic acid to the prostaglandinsPGG2 and PGH2. Since these two cyclic

    endoperoxides are the precursors of all other

    prostaglandins, the implications of cyclooxygenase

    inhibition are significant. Prostaglandin E1 is knownto be a potent py rogen (fever-causin g agent), and

    PGE2 causes pain, edema, erythema (reddening of

    the skin), and fever. The prostaglandin

    endoperoxides (PGG2 and PGH2) can also produce

    pain, and inhibition of their synthesis can thus

    account for the action of the nonsteroidal anti-

    inflammatory agents.

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    Most of the nonsteroidal anti-inflammatory drugs (NSAIDs) are

    carboxylic acids. Aspirin (8.69) (acetylsalicylic acid, ASA) has

    been used since the turn of the last century to reduce pain and

    fever, but the parent compound, salicylic acid, has been known

    and used since antiquity, owing to its common occurrence as aglycoside in willow bark. Acetylation merely decreases its

    irritating effect. Among the numerous other salicylates known and

    used, flufenisal (8.70) has a longer duration of activity and fewer

    side effects than aspirin.

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    Mefenamic acid (8.71) and flufenamic acid (8.72) are derivatives of

    anthranilic acid, while ibuprofen (8.73) and naproxen (8.74) are

    derivatives of phenylacetic and naphthylacetic acids, respectively.

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    Among indole derivatives, indomethacin (8.75) is very widely used despite side

    effects. Its indene analog sulindac (8.76) is a pro-drug, the active form being

    its SH derivative. Piroxicam (8.77) is a long-lasting anti-rheumatoid agent

    but can have serious gastrointestinal side effects. The once widely used

    phenylbutazone (8.78) derivatives have too many side effects and have falleninto disrepute.

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    Among the nonselective cyclooxygenase (COX) inhibitors,

    there is no clear-cut statistical evidence for the superiority of

    one or another of these useful drugs. Individual patients may

    do better with some than with others, and there are

    differences in side effects, primarily gastric bleeding and

    renal toxicity, which can be especially serious with the

    prolonged administration of high doses necessary in chronic

    diseases such as rheumatoid arthritis. Some of these

    compounds are powerful enough to be effective against themajor pain caused by malignancies.

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    Most of the nonsteroidal antiinflammatory drugs

    are carbocylic acids, Aspirin (acetylsalicylic acid,

    ASA), has been used since the turn of the century to

    reduce pain and fever, but the parent compound,

    salicylic acid, has been known and used since

    antiquity, owing to its common occurrence as a

    glycoside in willo bark. Acetylation merely

    decreases its irritating effect. Among the numerous

    other salicylates known and used, flufenisal has alongaer duration of activity and fewer side effects

    than aspirin.

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    In theory the selective COX-2 inhibitors may offer some advantages.

    There are at least two forms of the COX enzyme: COX-1 and COX-2.

    COX-1 is located in most tissues, including stomach and kidneys.

    COX-2, on the other hand, is undetectable in most tissues under

    physiological conditions. COX-2 is induced at sites of inflammation,

    secondary to the effects of cytokines. Accordingly, specific COX-2

    inhibitors, such as celecoxib (8.79) and rofecoxib (8.80), are less likely

    to cause stomach ulceration and gastrointestinal bleeding.Nevertheless, they still have the capacity to cause fluid retention and

    renal damage. More significantly, in 2004 it was recognized that COX-

    2 inhibitors may pose an increased cardiovascular risk. For example,

    rofecoxib was suddenly withdrawn from the market when it was noted

    that there was an increased relative risk for confirmed cardiovascularevents, including heart attack and stroke, beginning after 18 months

    of treatment, compared to placebo.

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    Anti-Leukotrienes as Anti-Inflammatory

    Agents for Asthma

    Like the other eicosanoids, the leukotrienes are also involved in inflammatorydiseases. Accordingly, leukotriene pathway inhibitors are emerging as

    important agents. Two fundamental approaches to the design of leukotriene

    pathway inhibitors have been pursued:

    1. Inhibitors of 5-lipoxygenase (to prevent leukotriene biosynthesis)

    2. Leukotriene receptor antagonists (to prevent leukotriene binding)

    Zileuton (8.81) is an inhibitor of 5-lipoxygenase; montelukast (8.82) and

    zafirlukast (8.83) are inhibitors of the leukotriene LTD4 receptor. All of these

    agents have demonstrated efficacy in the treatment of asthma, a common

    chronic inflammatory disease of the airways.

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    COOH COOH

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    OC

    COOH

    Aspirin

    CH3

    O

    OC

    COOH

    Flufenisal

    CH3

    O

    F

    Mefenemic acidand flufenamic acidare derivatives of anthranilic acid,

    while ibuprofen and naproxen are derivatives of phenyl acetic acid and

    naphthylacetic acid, respectively.

    NH

    COOH

    Mefenemic AcidCH3

    CH3

    NH

    COOH

    Flumefenemic AcidCF3

    CHCH3

  • 8/10/2019 I.FF.MC LECTURE ppt 15.ppt

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    HC

    COOH

    Ibuprofen

    CH3

    CH3

    CH3

    H2C

    CHCOOH

    Naproxen

    CH

    H3CO

    COOH

    Indomethazcin

    CH3

    H2C

    NH3CO

    C

    Cl

    O