7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 1/76
The Big Implications of
Pzer’s Little Blue Pill
Sildenal citrate: The
Revolutionary Bloc!uster"rug of the #$$%s
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 2/76
&rticle Titles
Sildenafl or Treatment o Erectile Dysunction inMen With Diabetes: A Randomized Controlled Trial
Rendell MS, Raer !, Wic"er #A, Smith MD, or theSildenafl Diabetes Study$rou%& JAMA.()))*+(-./:0+(10+2&doi:(3&(33(4ama&+(&.&0+(&
• 5ral Sildenafl in the Treatment o ErectileDysunction
Ir'in (oldstein) *+"+) Tom ,+ Lue) *+"+) -arin Padma./athan)
*+"+) Raymond 0+ Rosen) Ph+"+) 1illiam "+ Steers) *+"+) andPierre &+ 1icer) *+"+ for the Sildenal Study (roup
/ 3ngl 4 *ed #$$56 775:#7$8.#9%9*ay #9) #$$5"I:
#%+#%;<=/34*#$$5%;#9775>%%#
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 3/76
*ay 0ause Informationverload
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 4/76
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 5/76
1hat 'e’re going to do
• Part #6 The #% . minute Ph":"iscussion on the history of Pzer)the discovery of sildenal) drug
research and clinical trials) synthesisand !iochemistry of sildenal
• Part >6 The #% ? minute *":
&natomy and Physiology) Pathology)Biochemistry and Pharmacology ofsildenal6 Therapeutics
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 6/76
@Aitamin A
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 7/76
The Biggest /e's of #$$5
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 8/76
The Little Blue Pill
• P"3 inhi!itor used for the treatmentof erectile dysfunction C3"D andpulmonary arterial hypertension
CP&-D
• riginally a antiangial medication
• 0omes in >; mg) ;% mg and #%%mgvariants
• Taen # hour !efore intercourse6once daily
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 9/76
Aiagra Sales
• $>E of all 3" medications
Based on the 9th
Fuarterly ,iscalReport of Pzer
• G7%% million in sales
•
9%% %%% units sold
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 10/76
Pzer
#6ARMACE7T8CA9SRA;ED +D $95<A99= A>TER
!56S5 ? !56S5
6EAD@7ARTERS8 EW =5R;
C8T= CE5: 8A C&READ
.(&2<89985
>57DERs:C6AR9ES #>8BER ?
C6AR9ES ER6ART>57DED: (0),
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 11/76
The discovery of Sildenal
Daid
<ron
icholas
Terrett
Andre
<ell
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 12/76
The Story of Aiagra: &n vervie' of"rug Research and 0linical Trials
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 13/76
-o' much is needed to produce a
ne' drugH
• This is uite a hard uestion toans'er) !ut a study !y 4oe "i*asiJestimated that it cost on average
G5%%)%%%)%%% to develop a ne' drug• <hough not conrmed) estimates
for development of a ne' drug are
no' in the order of G%+; . > !illionJJJ"i*asi 4&) -ansen R1) (ra!o'si -(+ 4 -ealth 3con+ >%%7>>C>D:#;#.5;JJ&dams 0) Brantner A C>%%<D+ Health Af (Millwood) +. C>D: 9>%?5
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 14/76
The "rug Pipeline
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 15/76
Really) all in all) ho' much does it
costH
• Broen do'n) the cost !roadly 'orsout at
– &round G77; million in the preclinicalphases
– &round G9<8 million in the clinical trialphases
–&round G#%% million in Post approval
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 16/76
The 3ntire Process
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 17/76
*ore on 0linical Trials
• Clinical Trials hae a lon historyF een i not ac"noleded asClinical trials
• >ormal record o clinical trialsdates bac" to the time o the“Trialists”:• Dr& Gan 6elmontHs %ro%osal or a
thera%eutic trial o bloodlettin oreers I(2+J
•
Dr& 9indHs, a shi% sureon, trial ooran es ? limes or scur (K0K
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 18/76
3ven *ore on 0linical Trials
6istorical 6ihlihts o Dru Trials
• ()3): #aul Ehrlich 1 Ars%henamine
• ()+): AleLander >lemin 1 #enicillin
• ().: $erhard Doma" 1 Sulonamide• ()00: Schatz4<uie4Wa"sman F
Stre%tomycin
• <y ().3, the <ritish Medical Res& Councildeelo%ed a systematic methodoloy orstudyin ? ealuatin thera%euticinterentions
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 19/76
0ore 0omponents of 0linical Trials
• 8nole human subects
• Moe orard in time
• Most hae a com%arison C5TR59 rou%
• Must hae method to measureinterention
• >ocus on un"nons: eNect o medication
• Must be done beore medication is %arto standard o care
• Conducted early in the deelo%ment othera%ies
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 20/76
*ore 0omponents
• Must reie eListin scientifcdata ? build on that "nolede
• Test a certain hy%othesis
• Study %rotocol must be built onsound ? ethical science
• Control or any %otential biases
• Most study medications,%rocedures, and4or otherinterentions
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 21/76
Recruiting (uinea Pigs+++er+++Patients
• 8dentiy eliible%artici%ants
• EL%lain study
• #roide inormedconsent
• Reassess
eliibility• Assin to one
rou%
#artici%ants shouldbe told:
• May hae side
eNects -aderseeNects/
• Time commitment
•
<enefts ? ris"s• May ithdra at
any time
• Enrollment (33O
oluntary
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 22/76
Phases of 0linical Trials
• Most trials that inole nedrus o throuh a series oste%s:
–P(: EL%eriments in thelaboratory
–P+: 5nce deemed sae, o
throuh (10 %hases
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 23/76
Phases of 0linical Trials
• #hase 8: Small group K>%.5% for #sttime to evaluate safety) determinesafe dosage range M identify S3
• #hase 88: RL4tL ien to larerrou% I(33133J to confrmeNectieness, monitor SE, ?
urther ealuate saety
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 24/76
Phases of 0linical Trials
• #hase 888: RL4tL ien to een larerrou% I(,3331,333J to ulfll all o#hase 88 obecties ? com%are it to
other commonly used tLs ? collectdata that ill allo it to be used saely
• #hase 8G: Done ater rL4tL has beenmar"eted 1 studies continue to test
rL4tL to collect data about eNects inarious %o%ulations ? SE rom lonterm use&
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 25/76
Summary of Phases I.III
# Subs. Length Purpose % Drugs
Successfully
Tested
Phase I20 – 100 Seeral
!onths"anly Safety $0%
Phase II p toseeral100
Seeral!onths&2 yrs.
Short ter!safety' !anlyeffecteness
((%
PhaseIII
100s –seeral1000
1&) yrs. Safety* dosage+ effecteness
2,&(0%
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 26/76
Standards
ethical %rinci%les uide clinicalresearch:
• Res%ect or #ersons: Treatmento %erson as autonomous
• <enefcence: 8ssue re: %otentialconQict beteen ood o society
s& indiidual
• !ustice: Treatment o all airly ?all eually share benefts ? ris"s
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 27/76
3thical /orms
Sound study desins ta"e into account:
• Randomization or sharin o ris"s
• #ro%er use o %lacebo
• #rocesses to monitor saety o rL4tL
• Com%etent inestiators
• 8normed consent
• Euitable selection o %artici%ants• Com%ensation or study related
inuries
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 28/76
Bac to Aiagra
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 29/76
The Surprising 3Nects on Test
Su!Oects
• Studies 'ere done to see 'hat sideeNects 'ould come from increaseddosages+ Aolunteers reported !ac
'ith side eNects lie head aches)visual pro!lems) and prolonged
penile erections+
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 30/76
Sildenal citrate
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 31/76
IP&0 /omenclature
#.K9.ethoQy.7.C<)8.dihydro.#.methyl.8.oQo.7.propyl.#HpyrazoloK9)7.dpyrimidin.;.ylDphenylsulfonyl.9.methylpiperazine
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 32/76
Synthesis of Sildenal
#+ *ethylation of 7.propylpyrazole.;.car!oylicacid ethyl ester 'ith hot dimethy sulfate+
>+ -ydrolysis 'ith /a-
7+ /itration 'ith fuming /itric &cid
9+ 0ar!oQamide formation 'ith reuQing thionylchloride= /-9-
;+ Reduction of /itro group to &mino
<+ &cylation 'ith >.ethoQy!enzoyle chloride
8+ 0yclization
5+ Sulfonation to the chlorosulfonyl derivative
$+ 0ondesation 'ith #.methylpiperazine
* th l ti f 7 l l ;
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 33/76
*ethylation of 7.propylpyrazole.;.car!oylic acid ethyl ester 'ith hot
dimethy sulfate
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 34/76
-ydrolysis 'ith /a-
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 35/76
/itration 'ith oleum
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 36/76
0ar!oQamide formation 'ith reuQing thionyl chloride= /-9-
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 37/76
Reduction of /itro group toamino
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 38/76
&cylation 'ith >.ethoQy!enzoyle chloride
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 39/76
0yclization
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 40/76
Sulfonation to the chlorosulfonyl derivative
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 41/76
0ondesation 'ith #.methylpiperazine
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 42/76
Synthesis
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 43/76
0itric acid
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 44/76
1hy add citric acidH
• Sildenal is !asic+
• Reacting it 'ith citric acid yields thesalt sildenal citrate+
• &s a salt) it is solu!le in 'ater !roendo'n into citrate and sildenal ions+
• Ions are more reactive than non.ionsin the cytoplasm) therefore)sildenal’s !ioavaila!ility is greatlyincreased+
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 45/76
Sildenal citrate
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 46/76
#ART ( 5> T6E (31M87TEMED SC6559: S5ME <AS8C
67MA AAT5M=
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 47/76
Types of *uscles
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 48/76
The -eart
I t l St t f th
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 49/76
Internal Structures of the-eart
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 50/76
The 0irculatory System
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 51/76
The Brain
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 52/76
The /ervous System
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 53/76
&natomy of the *ale (enitals
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 54/76
The Internal Structures
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 55/76
Part > of the #% ? minute *":
Physiology and Biochemistry
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 56/76
-o' the heart pumps !lood
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 57/76
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 58/76
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 59/76
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 60/76
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 61/76
*ale -uman SeQual Response 0ycle
•30IT3*3/T
•
PL&T3&•R(&S*
•R3SLTI/
So 'hat are erections
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 62/76
So) 'hat are erectionsany'ayH
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 63/76
*edical denition
• &n erection Cclinically: %enileerection or %enile tumescenceD is aphysiological phenomenon of the male genitalia ofmany species) in 'hich the penis !ecomes rmer)
engorged and enlarged+ Penile erection is theresult of a compleQ interaction of psychological)neural) vascular and endocrine factors) and isoften associated 'ith seQual arousal or
seQual attraction) although erections can also !espontaneous+ The shape) angle and direction of anerection varies considera!ly in humans+
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 64/76
-o' erections occur
• pon seQual stimulation) theterminals of parasympathetic nervesrelease nitric oQide+
• The nitric oQide diNuses into thesmooth muscle cells and !ind 'iththe enzyme guanylate cyclase+
• (uanylate cyclase convertsguanosine triphosphate C(TPD intocyclic guanosine monophosphate
Cc(*PD+
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 65/76
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 66/76
-o' erections occur
• c(*P !inds to Protein inase ( CP(D'hich causes the smooth musclecells to relaQ) allo'ing for an ino'
of !lood+ P( 'ors !y manymechanisms) including lo'ering thecellular 0aU> levels+
• The ino' of !lood causes thesinusoids of the corpus cavernosumto enlarge) 'hich compresses the
penile veins+
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 67/76
-o' erections occur
• Therefore) there !ecomes acollection of !lood inside the penissmooth muscle tissue+
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 68/76
-o' does Aiagra 'orH
• Phosphodiesterase ; CP"3 ;D is the enzymethat catalyzes the hydrolysis of c(*P !acinto (TP+
•
Aiagra acts competitively 'ith c(*P at theactive site of P"3 ;+
• So) if Aiagra inhi!its P"3 ;) then there 'ill!e an accumulation of c(*P in smooth
muscle cells until the Aiagra is meta!olizedCmainly !y cytochromes in hepaticmeta!olismD+
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 69/76
Viagra shows good competitive kinetics with
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 70/76
Viagra shows good competitive kinetics withcGMP because of the structural similarities
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 71/76
Pharmacology
• Aiagra is rapidly a!sor!ed after oraladministration . Total Bioavaila!ility:9%E
• Its pharmacoinetics are doseproportional over the recommendedrange
• Aiagra is meta!olized mainly !yhepatic meta!olism and eQcretedmainly in the feces+
-o' Scientists Tested
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 72/76
-o' Scientists TestedSu!Oects
• Scientists assessed erections using aninstrument called Rigiscan) 'hich measureshardness and duration of erections+
• &lso) each su!Oect 'as given a survey)'hich measured the a!ility to achieveerections for suVcient seQual intercourse)and the a!ility to maintain erections afterpenetration+
• &lso) some su!Oects 'ere ased to create adiary to 'rite do'n any feelings or sideeNects they might have had+
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 73/76
0linical Results
• 3rectile dysfunction 'as attri!uted toorganic C;5ED) psychogenic C#8ED) ormiQed etiologies C>9ED+
• &fter < months of Aiagra treatment) thepercentages of men reportingimprovement in their erections are !elo':
rganic W <7EPsychogenic W 89E
*iQed W 5>E
Is this a 'onder drug or are there
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 74/76
Is this a 'onder drug) or are there
side eNectsH
• ne side eNect of Aiagra comes fromthe relatively high selectivity for P"3<+ &t pea plasma levels of Aiagra)
some su!Oects cannot distinguish!et'een green and !lue+
• In place!o controlled studies) only
>+;E of users discontinued the use ofAiagra !ecause of negative sideeNects+
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 75/76
Side 3Nects
• Some side eNects of Aiagra:
-eadache
,lushing
"yspepsia
/asal 0ongestion
"iarrhearinary Tract Infections
7/21/2019 Pfizer’s Blue Pill.pptx
http://slidepdf.com/reader/full/pfizers-blue-pillpptx 76/76
*aOor 0oncerns
• Because Aiagra is a vasodilator Calthough mainlylocallyD) it needs to !e used cautiously !ecause itlo'ers !lood pressure+
• Aiagra should not !e given to patients 'ho are taingnitrates) !ecause nitrates are also a strong vasodilator+
The use of !oth could cause maOor heart pro!lems+• &lso) the use of 0XP7&9 or P9;% inhi!itors C'hich are
the cytochromes responsi!le for Aiagra meta!olismD)greatly increases the ris of negative side eNects+
Some 0XP7&9 inhi!itors include 3rythromycin)0imetidine+
ne maOor P9;% inhi!itor is Ritonavir