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Aricept

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					Aricept (donepezil HCl)
         Team A
Background
   Most widely used Alzheimer’s drug
   Treats mild, moderate, and severe Alzheimer’s
   Alzheimer’s linked to low levels of Acetylcholine
    and Choline Acetyltransferase
   These low levels affect thought, speech, memory,
    and judgment.
   Marketed by Eisai, Inc. (manufacturer) and
    Pfizer, Inc.
A Review of Acetylcholine
   Acetylcholine receptor responds to the binding of the
    acetylcholine.
   Acetylcholine is synthesized by the enzyme choline
    acetyltransferase from the compounds choline and acetyl-
    coenzyme A.
   The enzyme acetylcholinesterase converts acetylcholine
    into choline and acetate.
Properties and Classification
   White crystalline powder
   Molecular weight of 415.96 g
   Non-competitive cholinesterase inhibitor
   Classification due to Mechanism of Action
Structure-Activity
         O2N                    O             N         N



                        1
                                                  IC50 = 12600 nM



         O2N                    O                       N




                        2
                                                  IC50 = 340 nM
                                O


                                                         N
          O2N                       N
                                    H



                                                   IC50 = 55 nM
                        3


                                    O


                                                              N
               O2SH2C                   N
                                        CH3


                            4                      IC50 = 0.6 nM
Structure-Activity
           O


                            N
                       N
                       H


                   5       IC50 = 560 nM



           O


                               N




                   7
                           IC50 = 530 nM


               O


                           N
                   N


                       8
                           IC50 = 230 nM
Structure-Activity
            O


                         N
                    N
                    H


                    5   IC50 = 560 nM


                O


                        N
                    N



                6
                        IC50 = 98 nM
                O


                        N
                N



                8
                         IC50 = 230 nM
Final Structure




    (±) 2,3-dihydro-5,6-dimethoxy-2-[(1-(phenylmethyl)-4-
      piperidinyl)methyl]-1H-inden-1-one hydrochloride
Mechanism Of Action
   Inhibits acetylcholinesterase from
    hydrolyzing acetylcholine
       Non-competitive inhibitor – does not bind to
        active site
 Increases acetylcholine concentration in
  synapse
 Increases cholinergic neurotransmission
 Improves cognitive function
Structure-Activity
   Vital interactions:
       Inandone ring of Aricept
        with Tryptophan 279
       Benzyl ring of Aricept
        with Tryptophan 84
       Piperidine ring of Aricept
        with Tyrosine 70, 121,
        334



                                     Structure March 1999, 7:297–307
Administration
   Film coated oral tablet, ODT (orally
    disintegrating tablet)
            5mg, 10mg
   Oral solution
       1 mg / mL
Pharmacokinetics
   Absorption
       Upper gastrointestinal tract
       Peak plasma level 3-4 hours
       Steady state plasma concentration in 15 days
   Distribution
       Travels in plasma through bloodstream
       Goes to many tissues and organs
            High among body tissues
            Liver
            Brain – target organ
Pharmacokinetics
   Metabolism
       Extensive
       Initial compound is active compound
       Metabolized through three reactions:
            O-demethylation at methoxy groups
            N-dealkylation at piperidine ring
            N-oxidation at piperidine ring
       Forms 14 metabolites – two are active inhibitors
       Metabolites cannot cross blood-brain barrier
Pharmacokinetics
   Elimination
       Half-life is 70 hours
       Urine and feces
            72% eliminated after 10 days
            17% unchanged drug
            Eliminated in urine as:
               Original drug
               One of 4 main metabolites
               One of many minor metabolites
Side Effects
   Considered mild and temporary
   Seen in 11% of patients
   Most common (5% or greater of patients) include:
       Nausea, diarrhea, insomnia, vomiting, muscle cramping,
        fatigue, anorexia
   May cause gastrointestinal bleeding in people
    already at risk for ulcers
   No evidence that it impairs fertility, is
    carcinogenic, or is mutagenic

				
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