753_Module4_AntiHypertensives by nuhman10

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									                                                              Phar 753, W-07




              PHARMACY 753, WINTER-2007



     MEDICINAL CHEMISTRY/PHARMACOLOGY



        CARDIOVASCULAR AGENTS

II: SYMPATHOLYTIC AND VASODILATOR
      ANTIHYPERTENSIVE AGENTS
                     Dr. J.F. Stevens


Reading assignment: Wilson and Gisvold 11th ed., pp 650-655




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ANTIHYPERTENSIVE AGENTS

INTRODUCTION:
   Hypertension arises when the arterial BP is sustained at an elevated level. Over 60 million persons in the
   US have elevated BP and it is contributing factor in > 106 deaths/yr.


Arterial BP is regulated by numerous factors, including:

   •   heart rate and stroke volume
   •   resistance of peripheral vascular network
   •   blood vessel elasticity
   •   blood volume and viscosity
   •   endogenous chemicals/hormones

   Because multiple regulatory systems control BP, coupled with the complexity of the factors causing
   hypetension, therapeutic agents that act to  BP work by a variety of mechanisms and act at a number of
   different sites

CLASSES OF ANTIHYPERTENSIVE AGENTS

Sympatholytic Agents



   •   peripherally-acting




   •   centrally-acting




Vasodilators

Renin-angiotensin system modulators

Ca2+ antagonists

Diuretics


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PERIPHERALLY-ACTING SYMPATHOLYTIC AGENTS

   •   adrenergic neuron blocking agents



   Rauwolfia alkaloids



       Used for centuries to treat insect bites, fever, insomnia and insanity

Major active component is Reserpine
                                                                                     N
                                                           H3 CO          N
                                                                          H H              H
                                                                                                    O
                                                                                H
                                                                                                               OCH3
                                                                          H3 CO 2C              O
                                                                                         OCH3
                                                                                                               OCH3
                                                                                                        OCH3



   Reserpine mechanism of action

       Causes depletion of biogenic amine neurotransmitters from peripheral adrenergic neurons


       Two proposed mechanisms

          •   reserpine inhibits NT transport into the storage vesicles




          •   reserpine destroys the NT storage vesicles




   CNS side effects




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Guanethidine (ISMELIN)                                          Guanedrel (HYLOREL)
                         H                                                            NH
                         N      NH
             N
                                                                          O
                                                                                 N         NH 2
                             NH 2                                                H

                                                                          O




Mechanism of action

   – Actively transported into the neuron via reuptake mechanism for NE
   – Initial step is to bind to storage vesicles and inhibit NE release
   – Displaces the neurotranmitter from the vesicle



These agents display some properties of a ‘false neurotransmitter’

   – found in storage vesicles
   – deplete levels of endogenous NT
   – released upon stimulation
   – exhibit low affinity for postsynaptic NT receptor



However – the initial sympathetic block occurs prior to NE depletion


No CNS side effects

NOTE: reliance on active transport mechanism for entry into neurons requires these agents not be taken
concurrently with drugs that block NT reuptake.




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-adrenergic antagonists

Blocking 1-adrenergic receptors inhibits vasoconstriction induced by catecholamine NTs.

Vasodilation occurs in both arterial and venous tissues.




Piperazinyl quinazolines

   General Structure

                                                                       R
                                                                   N
                                        H3CO           N       N

                                                           N
                                        H3CO
                                                       NH2




   Prototype is prazosin (MINIPRESS)
                                                   O


                                               N

             H3CO               N        N             O


                                    N
             H3CO

                                NH2



       1-selective

       Good oral availability
       Onset of action in 2-3 hrs



   Metabolized primarily by demethylation and glucuronidation



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Structure-Activity Relationships

   •   the piperazinyl-6,7-methoxyquinazoline nucleus is optimal

       – replacement of the OMe groups with methyls  activity


       – replacement of OMe groups with H, OH or methylendioxy group eliminates activity



   •   Groups on the piperazine ring can vary –


                 O                                                             O

                           O
       R=                                                           R=
                                                                                   O
                           O

         Doxazosin (CARDURA)                                               Terazosin (HYTRIN)




Other -antagonists indicated as antihypertensives

Phenoxybenzamine (DIBENZYLINE)



                           CH3
                 O
                       N
                                   Cl




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    Phentolamine (REGITINE)

       H 3C

                                   H
                                   N
                        N
                              N


                              OH



Tamsulosin (FLOMAX)

                                               >selective α1A-receptor antagonist
                                       O
     O
                                        O      >for treatment of benigne prostate hyperplasia (VSM relaxation
            O
                    N                  S       in prostatic region to improve micturition)
                    H                    NH2
                                   O
                 tamsulosin                    >less orthostatic hypotension




•   -Adrenergic Antagonists

    Complex and multiple mechanisms of action that lead to a decrease in blood pressure

    Include:
        – inhibition of central mechanisms controlling BP

         – reduction in cardiac output by acting directly at -receptors in the heart

         – inhibition of renin release by antagonizing-receptors in the kidney



    -receptor antagonists are used to treat all grades of hypertension

         – most appear to be equally effective

         – commonly combined with diuretics or ACE inhibitors




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CENTRALLY-ACTING SYMPATHOLYTICS

   First generation were -adrenergic agonists

   Original proposal was that they stimulated central 2-receptors which

       – inhibits release of NE

       – reduces sympathetic outflow from CNS

   Prototype is Clonidine (CATAPRES)




              Cl            Cl
                     N
                            NH
                      HN



Does not produce orthostatic hypotension associated with -antagonists

   Can act centrally AND peripherally

       At doses greater than required for central effects clonidine can activate  receptors in vascular
       smooth muscle and cause vasoconstriction.


       The result is a loss of the therapeutic effect at high doses


   Clonidine SAR

                              X    HN                                 X     N

                                        NH                                       NH
                                   N                                       NH


                              X’                                      X’
                                                                                ED20 (mg/kg)

       X = X’ = H                                                                  > 3.0

       X = Cl; X’ = H                                                                 1.0
       X = X’ = Cl                                                                    0.01

       X = X’ = Br                                                                    0.045

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       X = X’ = F                                                                    >3.0

       X = X’ = Methyl                                                                0.1

       X = X’ = Ethyl                                                                >3.0
       X = X’ = CF3                                                                   0.06


       ED20 refers to the IV dose necessary to lower the blood pressure by 20 mm Hg in the rabbit.




Clonidine metabolism: para-hydroxylation of phenyl ring and glucuronidation of hydroxyl group.
Metabolites cannot pass BBB and have no antihypertensive effect.



Other -agonists

   Guanabenz (WYTENSIN)                                                Guanafacine (TENEX)
             Cl                                                                 Cl
                        HN                                                                   HN
                   CH            NH 2                                                                NH 2
                    N    NH                                                                   NH
             Cl                                                                 Cl   O




   -Methyldopa (ALDOMET, METHYLDOPATE HYDROCHLORIDE)



                              NH 2
      HO
                                CH 3

                           CO 2H
      HO




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   mechanism of action

   –   first believed to function as a peripheral false neurotransmitter after conversion to -MeNE


   later evidence pointed to central activity

   •   dopa decarboxylase inhibitor studies

       – dopa decarboxylase inhibitors able to access the CNS block -methyldopa antihypertensive
         action


       – inhibitors that can’t cross BBB have no effect on antihypertensive action




   •   centrally-acting -antagonists block antihypertensive effect of -methyldopa




Second Generation Centrally-acting Sympatholytics

   Discrepancies noticed with central 2-agonist MOA for agents like clonidine and guanabenz


   •   why were guanabenz and guanfacine 10x less effective antihypertensives than clonidine but had 3 –
       10x higher affinity for 2 receptor and were more 2 selective?


   •   why did the later compounds still exhibit the same side effect profile as clonidine if they were more
       2 selective?

   Radiohistochemical studies show the central sites of action for clonidine are in the ventrolateral medulla

   •   found this region region of the brain does not contain many 2 receptors

   •   found that clonidine also binds to a novel class of receptors
                                                                        HN                    HN
       selective for imidazole and imidazoline containing
       compounds and the VLM is rich in these receptors.                       N                      N
       Distinct from adrenergic and histaminergic receptors.            R                    R
                                                                        imidazole            imidazoline
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       I1-imidazoline receptors



Highly selective I1 agonists have been developed

   Some are equipotent to clonidine in decreasing BP but show lower incidence of drymouth/sedation



Moxonidine


                   Cl   HN

             N                 N
    H3C                 NH
             N
                   OCH3



   Site of action is VLM

   – Agonism of the I1 receptor results in lowered catecholamine secretion and a reduction in renin
     and aldosterone levels


   – highest affinity at I1 receptor of known agonists

   – affinity for I1 vs 2 sites is 40 – 200x greater

   – long duration

   – not metabolized to any significant extent

   – less potential for BP rebound upon withdrawal


   – efficacy is similar to ACE inhibitors, Ca2+ antagonists and blockers at lowering BP




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Rilmenidine (HYPERIUM)


                     O

                           N
                    NH






        Slightly less potent than moxonidine

        Same pharmacological profile




ARTERIAL VASODILATORS

    Agents acting directly on smooth muscle to reduce arterial tone without affecting autonomic nervous
    system

    Effect is often compensated for by sympathetic reflexes – so -blockers are commonly coadministered


    Hydralazine (APRESOLINE)


                         NHNH 2


                               N

                               N




    •   One of first marketed orally-active antihypertensives in US

        – lost popularity due to side effect profile




        – adding on a -blocker so that dose of hydralazine could be reduced improved compliance


    •   appears to affect Ca2+ entry and Ca2+ release from intracellular stores


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   Diazoxide (HYPERSTAT)


                              N          CH 3


                                    NH
           Cl                 S
                          O        O




   –   orally available but only given IV



   •   Originated from thiazide diuretic SAR studies


       – initially believed that the decrease in BP observed with thiazides was only a result of diuresis

                removal of sulfonamide from 7 position of thiazide core eliminated diuresis but some of
                these compounds retained antihypertensive activity

                led to the development of diazoxide

Side effects:
        – can cause hyperglycemia


       – extended use can result in hypertrichosis




   Minoxidil (LONITEN, ROGAINE)



                                                           Used in cases of severe or refractory HTN
                      N


                  N                                        Side effects include reflex tachycardia

           H 2N       N           NH 2                     Na+ and H2O retention
                      O
                                                           hypertrichosis




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   Minoxidil requires metabolic activation to the O-sulfate


                                                      PAPS = 3’-phosphoadenosine-5’ phosphosulfate
 Sulfotransferase       H2N       N             NH2

                                  O         O
    PAPS
                                        S
                                            O
                                    O




   Clues to requirement for activation

       •    minoxidil has no direct action on vascular smooth muscle in vitro


       •    30-60 minute delay in the onset of antihypertensive action




Pinacidil
                                                                                            CH3
   Well documented K+ channel opener
                                                                                               CH3
                                                                                     HN
   Marketed extensively outside the US                                                         CH3
                                                                                NC           CH3
                                                                                     N     NH
   Sold as the racemic mixture but it is the R-(-) isomer that is active.



                                                                                         pinacidil




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                             MISCELLANEOUS NEW ANTIHYPERTENSIVE AGENTS
                             AND NEW TARGETS FOR TREATING HYPERTENSION

Fenoldopam mesylate (Corlopam®)
                                                                                          Cl
                                                                                    HO
Released in the US in 1999 for us in the short term control of severe
       hypertension in a hospital setting                                                           NH
                                                                                    HO

   Rapid onset and long duration

Acts as a peripheral dopamine D1-receptor agonist to cause systemic
       vasodilation                                                                       HO
   Can’t cross the blood-brain barrier so no central dopaminergic effects

   Also has some affinity for 5HT1 and 5HT2 receptors

Found to be more potent than nifedipine in a head-to-head trial



Ketanserin
                                                                                           O
   serotonin 5HT2 receptor antagonist                                   O
                                                                                    N
   very effective at reducing BP, especially in elderly                     N                            F

                                                                        N       O
   5HT2 antagonism alone cannot explain antihypertensive                H            ketanserin
   activity



V1 VASOPRESSIN RECEPTOR ANTAGONISTS

   Vasopressin is a peptide amide hormone with vasoconstricting action

   Nonpeptide antagonists are under development




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ENDOTHELIN RECEPTOR ANTAGONISTS

   Endothelins (ETs) are a family of peptides with complex actions on vascular smooth muscle

   ET-1 is a more potent vasoconstrictor than angiotensin II

    ETA receptor mediates vasoconstriction and ETB receptor modulates vasodilation and antiplatelet
activity

       Several nonpeptide ETA antagonists went into clinic in 1995 and 1996

   Bosentan (2001)

                  O
                  S NH
                             OCH3
                  O
                         O
                  N
          N
                    N    O
              N              OH




   Endothelin converting enzyme is also a target for developing new antihypertensive agents.




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