341rio lassbio 2012)lassbio.icb.ufrj.br/download/conferencias/potpourri_qm_mar2012.pdf · 10. l...
TRANSCRIPT
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Programa de Seminários
Pot-pourri de QuimMed
http://www.farmacia.ufrj.br/lassbio
Laboratório de Avaliação e Síntese de Substâncias Bioativas
Programa de Desenvolvimento de Fármacos - ICB
Eliezer J. BarreiroEliezer J. BarreiroEliezer J. BarreiroEliezer J. BarreiroEliezer J. BarreiroEliezer J. BarreiroEliezer J. BarreiroEliezer J. Barreiro
Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos – INCT-INOFAR
eliezer 2012
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“ ...medicinal “ ...medicinal chemistschemists todaytoday livelive in in
excitingexciting times...times...
theirtheir work work cancan havehave a beneficial a beneficial theirtheir work work cancan havehave a beneficial a beneficial
effecteffect onon millionsmillions ofof
sufferingsuffering patientspatients –– surelysurely anan importantimportant
motivatingmotivating factorfactor for for anyany scientistscientist...”...”
TheThe Role Role ofof thethe Medicinal Medicinal ChemistChemist in in DrugDrug Discovery Discovery –– ThenThen andand NowNow, ,
NatureNature Rev. Rev. DrugDrug DiscDisc. . 20042004, , 3,3, 853.853.
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O O processoprocesso dada invençãoinvenção de de novosnovos fármacosfármacos
é é muitomuito complexocomplexo……
Os Os medicamentosmedicamentos
sãosão bens bens industriaisindustriais!!
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EJ Barreiro & AKN Alencar (Dissertação de Mestrado, PPGFQM, ICB-RJ, 2012)
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É a primeira substância de umaÉ a primeira substância de umasérie congênere série congênere –– i.e.i.e. estruturalmente estruturalmente
relacionada relacionada –– que apresentou perfilque apresentou perfilterapêutico adequado terapêutico adequado –– i.e.i.e. ativo emativo emmodelos farmacológicos validados modelos farmacológicos validados in in
Conceito de compostoConceito de composto--protótipoprotótipo
modelos farmacológicos validados modelos farmacológicos validados in in
vivovivo -- que pode ser subsequentemente que pode ser subsequentemente otimizado por modificações otimizado por modificações
moleculares racionais.moleculares racionais.
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O S
Simplificação
molecular
CC1313HH1010NN22OO33SS
MW 274MW 274
O
ON
N
H H
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Pat
ente
obt
ida
Pat
ente
obt
ida
LASSBioLASSBio--294 294
PatentPatent (USPTO) 7.091.238 (15/08/2006) (USPTO) 7.091.238 (15/08/2006)
Pat
ente
obt
ida
Pat
ente
obt
ida
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O
N
N
N
N
N
N NH2
O
N
N
NO
O
NN
S
SimilaridadeSimilaridade molecular & molecular & mecanismomecanismo de de açãoação
Catalog SigmaCatalog Sigma
S4568S4568
O
O
O
N
H
N
S
LASSBio-294
SCH-58261
Antagonista competitivo de A2A
Ki = 1,3 nM
N
N
N
N NH2
O
O
N
H
7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-
[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine
19991999
LASSBio-294E
LASSBio-897
Receptores de Adenosina A2A
IC50= 9.5 µM
IC50= 4.6 µM
CEREP101
Alvos Moleculares
20092009
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EstudosEstudos de de otimizaçãootimização do do protótipoprotótipo
DissecaçãoDissecação molecular; molecular;
PreservarPreservar o o grupamentogrupamento farmacofóricofarmacofórico ((GrFGrF););
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1. RT Sudo, G Zapata-Sudo, EJ Barreiro, The new compound, LASSBio 294, increases the
contractility of intact and saponin-skinned cardiac muscle from Wistar rats, Br. J.
Pharmacol., 134, 603-613 (2001) (Times Cited: 14)
2. H Gonzalez-Serratos et al., A novel thienylhydrazone, (2-thienylidene)3,4-
methylenedioxybenzoylhydrazine, increases inotropism and decreases fatigue of skeletal
muscle, J. Pharmacol. Exp. Ther., 299, 558-566 (2001) (Times Cited: 13)
3. CLM Silva, F Noel, EJ Barreiro, Cyclic GMP-dependent vasodilatory properties of
LASSBio 294 in rat aorta, Br. J. Pharmacol., 135, 293-298 (2002) (Times Cited: 16)
4. EJ Barreiro, Strategy of molecular simplification in rational drug design: The discovery of a
new cardioactive agent, Quim. Nova, 25, 1172-1180 (2002) (Times Cited: 15)
5. G Zapata-Sudo et al., Thienylhydrazone derivative increases sarcoplasmic reticulum Ca2+
release in mammalian skeletal muscle, Eur. J. Pharmacol., 470, 79-85 (2003) [Times
Cited: 3]Cited: 3]
6. H Gonzalez-Serratos et al., The thienylhydrazone, (2 '-thienylidene)3,4-
methylenedioxvbenzoylhydrazine (LASSBio-294), develops fatigue resistance and has a
positive inotropic effect in mammalian skeletal muscle, Biophys. J., 86, 225A-225A Suppl.
S (2004 ) [Times Cited: 0]
7. AG Silva, G Zapata-Sudo, AE Kummerle et al., Synthesis and vasodilatory activity of new
N-acylhydrazone derivatives, designed as LASSBio-294 analogues, Bioorg. Med. Chem.,
13, 3431-3437 (2005) [Times Cited: 33]
8. AE Kummerle et al., Studies towards the identification of putative bioactive conformation
of potent vasodilator arylidene N-acylhydrazone derivatives, Eur. J. Med. Chem., 44, 4004-
4009 (2009) [Times Cited: 14]
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9. G Zapata-Sudo et al., Pharmacological Characterization of (3-Thienylidene)-3,4-
Methylenedioxybenzoylhydrazide: A Novel Muscarinic Agonist With Antihypertensive
Profile, Am. J. Hypert., 23, 135-141 (2010) [Times Cited: 1]
10. L Pol-Fachin et al., Characterization of the conformational ensemble from bioactive N-
acylhydrazone derivatives, J. Mol. Graph. Model., 28, 446-454 (2010) [Times Cited: 0]
11. EO Carneiro et al., Structure-based prediction and biosynthesis of the major mammalian
metabolite of the cardioactive prototype LASSBio-294, Bioorg. Med. Chem. Lett., 20,
3734-3736 (2010 ) [Times Cited: 3]
12. FCF Brito et al Novel thienylacylhydrazone derivatives inhibit platelet aggregation through
cyclic nucleotides modulation and thromboxane A(2) synthesis inhibition, Eur. J.
Pharmacol., 638 , 5-12 (2010 ) [Times Cited: 3]
13. AE Kummerle et al., LASSBio-294, A Compound With Inotropic and Lusitropic Activity,
Decreases Cardiac Remodeling and Impro, oves Ca2+ Influx Into Sarcoplasmic Reticulum
23After Myocardial Infarction, Am. J. Hypert., 23, 1220-1227 (2010) [Times Cited: 2]
14. AGM Fraga, LL Silva, CAM Fraga, EJ Barreiro, CYP1A2-mediated biotransformation of
cardioactive 2-thienylidene-3,4-methylenedioxybenzoylhydrazine (LASSBio-294) by rat
liver microsomes and human recombinant CYP enzymes, Eur. J. Med. Chem., 46, 349-
355 (2011) [Times Cited: 1]
15. RC Braga, ACB Tôrres, CB Persiano, RO Alves, CAM Fraga, EJ Barreiro, V Oliveira,
Determination of the cardioactive prototype LASSBio-294 and its metabolites in dog
plasma by LC–MS/MS: Application for a pharmacokinetic study, J. Pharm. Biomed. Anal.,
55, 1024–1030 (2011) [Times Cited: 1]
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Como Como chegamoschegamos àsàs NAH?NAH?
SP Janssens et al, Cyclooxygenase and lipoxygenase inhibition
by BW-755C reduces acrolein smoke-induced acute lung injury,
Journal of Applied Physiology 1994, 77, 888
C Bertez et al., Dual inhibition of cyclooxygenase and lipoxygenase
by 2-acetylthiophene 2-thiazolylhydrazone (CBS-1108) and effect
on leukocyte migration in vivo, Biochem Pharmacol. 1984, 33, 1757
N
N
H2N
CF3
a
on leukocyte migration in vivo, Biochem Pharmacol. 1984, 33, 1757BW-755c
HibridaçãoHibridação
molecularmoleculara + ba + b
NN--arilidrazonaarilidrazona
N
N N
H
N Ar
NO2
C Viegas-Jr, A Danuello, VS Bolzani, EJ Barreiro, CAM Fraga, Molecular hybridization: a useful tool in the design
of new drug prototypes, Curr. Med. Chem. 2007, 14, 103 [46 citações]
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NAH
NitroNitro--azolaazola
NAH
EJ Barreiro et al., A química medicinal de N-acilidrazonas: novos compostos
protótipos de fármacos analgésicos, antiinflamtórios e anti-trombóticos, Quim.
Nova 2002, 25, 129 [20 citações]
DiazocetonaDiazocetona
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N
N
O
NH
N H
N
N
O
NH
N Ar
HAr
HA
ZE
N4
PropriedadesPropriedades
estruturaisestruturais
configuraçãoconfiguração
N
N
O
HN
N
HAr
N
N
O
HN
N Ar
H3
5
3
5
N
O N
N
N
4
conformaçãoconformação
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B
i
o
i
s
o
s
B
i
o
i
s
o
s
BioisosterismoBioisosterismo & & quimiodiversidadequimiodiversidadeDerivados Derivados NN--acilidrazônicosacilidrazônicos (NAH)(NAH)
EJ Barreiro EJ Barreiro et alet al., ., Quim. NovaQuim. Nova 20022002, , 2525, 129, 129--148148
s
t
e
r
i
s
m
o
s
t
e
r
i
s
m
o
LM Lima, EJ Barreiro, Bioisosterism: a useful strategy for molecular modification and drug
design, Curr. Med. Chem. 2005, 12, 23 [161 citações]
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Quimioteca “combinatória”de NAHQuimioteca “combinatória”de NAH
Ar1 NH
O
N Ar2
Quimioteca 7 x 7 =
Bom perfil farmacocinéticoBom perfil farmacocinético
e farmacodinâmico e um importante perfil e farmacodinâmico e um importante perfil
antiinflamatório e analgésicoantiinflamatório e analgésico
Quimioteca 7 x 7 =
49 N-acilidrazonas
Grupos com diferentes σσσσ Hammett: -0,4 a +0,3Refratividade molar: 25 a 39 cm3/molGrupos aceptores ou doadores de ligação hidrogênioGrupos com diferentes perfis de hidrofilicidade
QuimiotecaQuimioteca ::
98 98 NN--acilidrazonasacilidrazonas
QuimiotecaQuimioteca ::
98 98 NN--acilidrazonasacilidrazonas
AE AE KummerleKummerle, , TeseTese de de DoutoramentoDoutoramento, , InstitutoInstituto de de QuímicaQuímica, UFRJ, 2009, UFRJ, 2009
NN--metilaçãometilação
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DiversidadeDiversidade
químicaquímica
Restrição Conformacional
AE Kummerle, MV Martins, M Schmitt, ALPMiranda, CAM Fraga, J-J Bourguignon, EJ Barreiro, Design, synthesis and
analgesic properties of novel conformationally-restricted N-acylhydrazones, Bioorg.Med.Chem.Lett. 2009, 19, 4963 [3
citações]
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NAH antimaláricoNAH antimalárico
Un MissUn Miss
M J M J AlvimAlvim--Gaston, M A Avery, E J Barreiro, 1999 (Gaston, M A Avery, E J Barreiro, 1999 (resultadosresultados nãonão publicadospublicados))
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Bioorg. Med Chem. Bioorg. Med Chem. 20122012, , 2020, 2158, 2158--21712171
furoxanasfuroxanas
LASSBioLASSBio--294294 LASSBioLASSBio--206206 LASSBioLASSBio--246246
FuroxanylFuroxanyl--NN--acylhydrazonesacylhydrazones
42 new compounds42 new compounds
MolecularMolecular
hybridizationhybridization
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Do LASSBioDo LASSBio--259 ao LASSBio259 ao LASSBio--445...445...
BióforoBióforo
naturalnatural
benzodioxolabenzodioxola
BispirazolaBispirazola
N
N
H3C
N
NH
N
CH3
S
O
O
CH3
O
ONH
S
O
O
H3C
1996 *1996 * 20002000
19821982--safrolsafrol
O
OCH2
LiteraturaLiteratura de de patentespatentes
1995-flosulido* AS Lages, 23 de setembro de 1996* AS Lages, 23 de setembro de 1996
LASSBio-259 LASSBio-445
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DesenhoDesenho molecular de molecular de derivadosderivados bispirazólicosbispirazólicos
OCH2 O
CH2
O
Nova relaçãoNova relação
bioisostéricabioisostérica
* A.S. Lages, K. C. M. da Silva, A. L. P. Miranda, C. A. M. Fraga & E. J. Barreiro,
"Synthesis and Pharmacological Evaluation of New Flosulide Analogues, Synthesized
from Natural Safrole", Bioorganic Medicinal Chemistry Letters, 8, 183-188 (19981998) [21 citações]
ONH
S
LASSBio-259 LASSBio-257
OS
HN
O
O
CH3O
O
H3C
retroretro--isostéroisostéro
Indanona /Indanona /
benzodioxolabenzodioxola
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DesenhoDesenho molecular de molecular de derivadosderivados bispirazólicosbispirazólicos
N
N
H3C
Cl
19951995--CelecoxibeCelecoxibe
19991999 -- CelebraCelebraRR
sistemasistema terfenílicoterfenílico33--metilmetil--55--clorocloro--
NN--fenilpirazolafenilpirazola
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unidadeunidadefarmacofóricafarmacofórica
GFGF
sistema terfenílico
NN
H3C
N
N
CH3
H3CS
O O
NH2NN
H3C
N
SO
O NH2
N
CH3
CH3
NN
F3C
SO
O NH2
H3C
DesenhoDesenho molecular de molecular de derivadosderivados bispirazólicosbispirazólicos
NN
H3C
S
O
O
NH2
N
N
CH3
CH3
sistema bispirazólico
TransposiçãoTransposiçãodo do GFGF
celecoxibecelecoxibeGFGF
Novo padrão molecularNovo padrão molecular
NN
H3C
N
N
CH3
H3CNH
SCH3
O
O
NN
H3C
N
N
R
R'NH
SCH3
O
O
Novo Novo padrãopadrão molecular originalmolecular original
bispirazolabispirazola
SérieSérie
congênerecongênere
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M. P. M. P. VelosoVeloso, , TeseTese DoutoradoDoutorado, , InstitutoInstituto de de QuímicaQuímica, UFRJ, 2000, UFRJ, 2000
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AR dos Santos et al., Atropoisomerismo: o efeito da quiralidade axial em
substâncias bioativas, Quim. Nova 2007, 30, 125
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A busca por novos simbióticos...
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