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XXV Encontro Regional da SBQSBQ-MG

12-14 de novembro de 2011


Universidade Federal de Lavras

A
A QUMICA MEDICINAL
E A DESCOBERTA DE NOVOS FRMACOS:
o exemplo do INCTINCT- INOFAR
Eliezer J. Barreiro
Professor Titular
UFRJ

Laboratrio de Avaliao e Sntese de Substncias Bioativas


Instituto Nacional de Cincia e Tecnologia
de Frmacos e Medicamentos
INCT--INOFAR
INCT

eliezer 2011

D
e
f
i
n
i

estuda os fatores moleculares relacionados ao


modo de ao dos frmacos,
incluindo a compreenso da relao
entre a estrutura qumica e a atividade (SAR),
alm das propriedades que governam sua
absoro, distribuio,
IUPAC

metabolismo, eliminao (ADME)

http://www.iupac.org

Chemistry and Human Health Division (VII)


Subcommittee on Medicinal Chemistry and Drug Development.

e toxicidade.
Eur. J. Med. Chem
Chem.,
., 31
31,, 747 (1996)

C. R. Ganellin et al., Eur. J. Med. Chem


Chem.. 2000, 35, 163; A. Monge et al., Eur. J. Med. Chem
Chem.. 2000, 35, 1121

...medicinal chemists today live in


exciting times...
their work can have a beneficial
effect on millions of
suffering patients surely an important
motivating factor for any scientist
scientist...
...
The Role of the Medicinal Chemist in Drug Discovery Then and Now
Now,,
Nature Rev. Drug Disc
Disc.. 2004
2004,, 3, 853.

Cronologia histrica da Qumica Medicinal


1955 C. roseus
1996 - Wermuth

1949 - Laborit
1958 - Burger

1911 - Fourneau

http://ejb-eliezer.blogspot.com
http://ejbParadigma de Ehrlich & Fischer, Primeiro Paradigma da Qumica Medicinal

O bero da Qumica Medicinal


S to v a rso l
C A S 9 7 -4 4 -9

OH

As

OH

Ernest Fourneau

H3C

Institut Pasteur (1887)

N
H

1872-1949

OH

1911- Laboratoire de Chimie Thrapeutique


Diretor: Emile Roux
1911--1944 Jacques Trfoul (1897
1911
(1897--1977)
Threze Trfoul (1892
(1892--1978)
Germaine Benoit (1901
(1901--1983)
Federico Nitti (1903
(1903--1947)

Prmio Nobel de
Fisiologia/Medicina
1957
Daniel Bovet
1907-1992 *

*Farmacutico suio
Doutor h.c. UFRJ

Sulfonamidas,
anti--histamnicos.
anti

Curare: SAR

J-P Fourneau, Ernest Fourneau foundateur de la Chimie Pharmaceutique


franaise , Revue de lHistoire de la Pharmacie, t.XXXIV, no 275, 335-355

J. Med Chem.
Chem. 1978
1978,, 21
21,, 1

Prof. Alfred Burger


(1904-2000)

University of Virginia
EUA
1958 fundou o Journal of the Medicinal and
Pharmaceutical Chemistry depois Journal of
Medicinal Chemistry
An Editors Commentary on the Birth of a Journal,
J. Med. Chem. 1991
1991,,34
34,, 22-6

O processo da descoberta
descoberta//inveno de frmacos

Atualmente, os novos
frmacos, capazes de
atuarem em qualquer
alvo--teraputico
alvo
teraputico,, so
descobertos/inventados
por planejamento
racional..
racional

EJ Barreiro, CAM Fraga, ALP Miranda, Estratgias em Qumica Medicinal para


o Planejamento de Frmacos, Braz. J. Pharm. Sc., 37, 269269-292 (2001).

Segundo paradigma da QuimMed

O tratamento de uma patologia multifatorial


(e.g. doenas crnicas no transmissveis
transmissveis,,
cncer,,
cncer

metablicas,

etc
etc))

com

frmacos

planejados para alvos teraputicos nicos


(Primeiro paradigma da Qumica Medicinal ou
Paradigma de Ehrlich & Fischer
Fischer)) ser sempre
paliativo! Estas patologias requerem frmacos
duplos,, mixtos,
mixtos, mltiplos ou
multi--alvos
multi
alvos,, i.e. duplos
simbiticos..
simbiticos

The multiple
multiple--target lead design

Segundo paradigma da Qumica Medicinal

Cidade Universitria, ilha do Fundo,


Rio de Janeiro, RJ

Creado em 19/04/1994 Laboratrio de Avaliao e Sntese de Substncias Bioativas

eliezer 2010

hit/ligante

Estratgias de
desenho molecular

validao precoce do
alvo--teraputico
alvo

MAPK
MMP

* TNFTNF- = Tumor necrosis factorfactor-alpha

The Target Election: TNFTNF-


TNF--
TNF

druggable target
validated
TNF-- is a cytokine that appears rapidly in response to inflammatory injury
TNF
PC Taylor, Pharmacology of TNF blockde in RA and other chronic inflammatory diseases
diseases,, Curr
Curr.. Op. Pharmacol
Pharmacol..
2010,, 10
2010
10,, 308

Anti--TNF
Anti
TNF Therapies
*

PC Taylor, Pharmacology of TNF blockade in rheumatoid arthritis and other chronic inflammatory
diseases, Curr
Curr.. Op. Pharmacol.
Pharmacol. 2010
2010,, 10,
10, 308

* proteinprotein-based injectable antianti-TNF


TNF therapies

2-(2,6(2,6-DioxoDioxo-3-piperidinyl)
piperidinyl)-1H-isoindole
isoindole--1,3(2H
1,3(2H)dione

Wilhelm Kunz,
Kunz, 1953
Herbert Keller
Keller,, 1953
CNS, 1957
Frances Kelsey
Kelsey,, 1961
Gilla Kaplan, 1991 (TNF
(TNF--)
Elisabeth Sampaio,1997

Thalidomide
Anti--TNF
Anti
TNF-- IC50 = 200 M
TNF

OMe
O
N

Apremilast,, Phase II, Celgene (2009)


Apremilast

O
S

NH

H3C

H-W Man et al
al.,
., J. Med. Chem.
Chem. 2009, 52, 1522

OEt

H3C

Second Target Election:PDEElection:PDE-4


Serine/threonine kinase cascade

The pathogenesis of inflammation


Phosphodiesterase-4 is
Phosphodiesterasepredominant in the inflammatory
cells

PDE = Phosphodiesterase

M. D. Houslay, P. Schafer, P.; K. Y. J. Zhang, PhosphodiesterasePhosphodiesterase-4 as a therapeutic target, Drug Discovery Today
2005,, 10, 1503; B. J. Lipworth, Phosphodiesterase2005
Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary
disease, Lancet 2005
2005,, 365
365,, 167

Alvo teraputico validado


ArifloR,
SB-207,499

Ruflomilast
Cl
N

O
O
N
H
Cl
O

CHF2

DaxasR
Aprovado
2011

pyridine-benzamide

Recent advances on phosphodiesterase 4 inhibitors for the treatment of


asthma and chronic obstructive pulmonary disease
A. Kodimuthali
Kodimuthali,, S. S. L. Jabaris,
Jabaris, M. Pal
J. Med. Chem. 2008
2008,, 51,
51, 5471

O
H3C
H3C

O
S

NH

Arilsulfonamide

PDE-4i IC50 = 4.3 M


5

Patent US 5728712 , Application Number US/08/650672; 20 May, 1996


J. G. Montana et al
al.*,
.*, Arylsulfonamides
Arylsulfonamides as selective PDEPDE-4 inhibitors
inhibitors,
,
Bioorg.. Med. Chem.
Bioorg
Chem. Lett.
Lett. 1998
1998,, 8, 2635

* Chiroscience Ltd,
Ltd, Cambridge Science Park, Cambridge, UK

The design of new dual agent with


toxicophore
O
N

anti--TNF
anti
TNF activity & PDE-4i

O
NH

sulfonamide

O
A

phthalimide

molecular
N

B
O
H3CO

sulfonamide

aryl

hybridization

S
N

O
S

phthalimide

isosteres
C

H3CO
aryl

N
H

lipophylic
N
CH3

S
Montana et al., 1998
, , RM

Bioisosterismo

Lidia M. Lima (LASSBio


(LASSBio),
), PhD Thesis,
Thesis, IQIQ-UFRJ, Br., 2001

Effect of compound LASSBio 468 (50 mg/kg, i.p


i.p.)
.) on TNFTNF- levels
and neutrophils influx (BALB/c of mice lungs)

50% more active than thalidomide

Vera G Koatz
IBqM,, Universidade Federal do Rio de Janeiro
IBqM

Effect of new compounds and thalidomide on neutrophils


influx,, induced by LPS into BALB/c of mice lungs
influx
(10 mg/kg,
mg/kg, DMSO; i.p.)
i.p.)
DMSO

Results are expressed as means SEM of seven animals.


Vera G Koatz
IBqM,, Universidade Federal do Rio de Janeiro
IBqM

TNF-- ED50 2,5 mg/Kg


TNF

O
N

O
S O
N

PDE--4 inhibitor
PDE

Dr Claire Lugnier (CAPES


(CAPES--COFECUB; LASSBio
LASSBio--Strasbourg)
Strasbourg)

S
C18H16N 2O4S2

Universit Louis Pasteur, Strasbourg


Strasbourg,, FR.
Laboratoire de Pharmacologie et de Physicochimie des Interactions
Cellulaires et Molculaires.
Molculaires.

IC50 = 13,5
13,5M
cf. PDE
PDE--1, 2, 3, > 150 M;
a) L. M. Lima et al., Synthesis and Anti-inflammatory Activity of Phthalimide Derivatives, Designed as
New Thalidomide Analogues, Bioorg. Med. Chem. 2002, 10, 3067;
b) M. S. Alexandre-Moreira et al., LASSBio-468: a New achiral Thalidomide Analogue which Modulates
TNF- and NO Production and Inhibit Endotoxic Shock and Arthritis in Animal Model, International
27
Immunopharmacology 2005, 5, 485.

LASSBio--468
LASSBio
A new symbiotic antianti-inflammatory agent
LASSBio-468 is a new dualLASSBiodual-target
anti--inflammatory lead
anti
lead--compound
compound,,
active at TNFTNF- production and
with inhibitory activity on PDEPDE-4,
as originally planned. LASSBioLASSBio-468
is structurally simple derivative, easy
to synthesized at good overall yield
and 0.5 M scale. This new achiral
compound presents immunomodulatory activity
without antianti-proliferative effect
effect,, in contrast to THLD.
LASSBio--468 is an useful leadLASSBio
lead-compound to
treatment of chronicle inflammatory disorders as
rheumatoid arthritis and shock septic syndrome.
syndrome.
L. M. Lima et al., Synthesis and Anti-inflammatory Activity of Phthalimide
Derivatives, Designed as New Thalidomide Analogues, Bioorg. Med. Chem. 2002, 10, 3067
A. L. Machado et al., Design, Synthesis and anti-inflammatory activity of novel phthalimide derivatives,
structurally related to thalidomide, Bioorg. Med. Chem. Lett. 2005, 15, 1169

The discovery of new dual lead


lead--compounds
LASSBio--468
LASSBio
Desenhado por
hibridao molecular
PDE--4
TNF-- PDE
TNF
TNF-- ED50 2,5 mg/Kg
TNF
PDE--4 IC50 = 13,6 M
PDE
Metabolism
studies

LASSBio--596
LASSBio
L. M. Lima, P. Castro, A. L. Machado, C. A. M. Fraga
Fraga,, C. Lugnier
Lugnier,, V. L. G. Moraes
Moraes,, E. J. Barreiro, Synthesis and AntiAnti-inflammatory
activity of Phthalimide Derivaatives
Derivaatives,, Designed as New Thalidomide Analogues, Bioorg
Bioorg.. Med. Chem
Chem.. 2002, 10, 3067.

NH2

O
ClSO3H

O
anidrido ftlico
C8H4O3

0oC a t.a. at 60oC

120 C
1h
(2M)

(1M)
O

HN

O
O
N

1h

O
C14H9NO2

O
S

O
Cl

CH2Cl2

C14H8ClNO4S

1h

LASSBio-468

0,4M

C18H16N2O4S2

0,35M

13

N
S

KOH / HOH
N
H
CO2H
LASSBio-596
C18H18N2O5S2

O
S

O
N

NEt3

CH3OH
1h

Rendimento global: 29%

C, 1H RMN / IV / UV / EM
HPLC
calorimetria diferencial
de varredura (DSC)
CHN
Difrao de Raios-X

LASSBio--596
LASSBio

O
S

O
N
H

N
S

CO2H
LASSBio--596
LASSBio
anti--fibrogenic
anti

Annual Activities Report


Interdisciplinar & multimulti-team
research projects
Radical innovation
pain,, inflammation,
pain
inflammation,
asthma,, CNS
asthma
CNS,,
neglected diseases,
diseases,
cardiovascular system,
system,
anticancer
Incremental innovation
SUS (BR healthcare)
new generic drugs
www.inct--inofar.ccs.ufrj.br/download/aar/2010.pdf
www.inct

INCT-INOFAR
Governance committee

Dr Simon Campbell

Foreign scientific consultants

Research partners

INCT-INOFAR

Atorvastatina
1991

HO

Sintetizada, em 1985, por Bruce Roth


[B. D. Roth, "The discovery and development of
atorvastatin,, a potent novel hypolipidemic agent,
atorvastatin
Prog.. Med. Chem. 2002
Prog
2002,, 40
40,, 1
1
22]

Patente US 5273995 Pfizer (1991):


12 etapas = 4,2%
Nova sntese Prof. Luiz Carlos Dias &
Dr Adriano S Vieira,
Vieira, IQ
IQ--UNICAMP,
em 2010
2010,, pelo INCT
INCT--INOFAR:

Incremental
Innovation
CO2H
OH
CH3

F
N

CH3
O
HN

11 etapas = 19,3%

super blockbuster
blockbusterdrug
LC Dias, A S Vieira, EJ Barreiro, Processo de obteno
de atorvastatina clcica utilizando novos intermedirios
PI 018110015039 (protocolado
(protocolado no INPI, em 25/04/2011)

Sunitinibe

Incremental
Innovation

2006
SutentR
Sintetizado, em 1999, pela Pfizer
Patente de 2001 (US)
Inibidor BCR
BCR
ABL TyrTyr-quinase
Indicado para Ca
Ca--estmago/rim
estmago/rim

50 mg / 28 caps ca. R$ 20.837,90

Vendas de tinibes no
mercado
norte--americano
norte
americano::

US$ 18,5 bi (2009)


Importaes
ca.
ca. US$ 3 milhes
milhes//ano

Nova sntese Prof. Angelo da Cunha


Pinto & Dr Brbara Vasconcellos
da Silva,
Silva IQ-UFRJ, em 2011, pelo
INCT-INOFAR
S Aggarwal, Nature Rev Drug Discov 2010, 9, 427

O Caminho
Caminho das ndias
ndias dos
nossos frmacos (genricos!)
genricos!)
Precisamos resolver, com urgncia
urgncia,, a grave situao
de dependncia das importaes de frmacos
frmacos,,
invertendo o sentido do atual Caminho das ndias
ndias

Inovao incemental

Biolab Sanus Farmaceutica Ltda


Cristlia Produtos Qumicos Farmacuticos Ltda
EMS - Sigma Pharma
Eurofarma Laboratrios Ltda
Genom Farmacutica Ltda
Laboratrios BIOSINTTICA
Laboratrio Neo Qumica Indstria Farmacutica Ltda
Laboratrio Teuto Brasileiro
LIBBS Farmacutica
Medley S/A Indstria Farmacutica
Mantecorp
Zambon Laboratrios Farmacuticos Ltda

A equipe do INCTINCT-INOFAR

Universidade Federal do Rio de Janeiro, maro 2011

Primeira reunio de avaliao e acompanhamento de 2011

Consideraes
Finais
For all the efforts to industrialize and automate
discovery,, history suggests drug discovery is art
discovery
as well as science and relies heavily on the skill
of experienced drug hunters
hunters...
...
Charles H. Reynolds
J&J Pharmaceutical Research and Development, Spring House, Pa
em Pharma's Road Ahead , C&EN
C&EN,, Volume 84, Issue 25, June 19, 2006

07 October 2009 vol 1, issue 1, 95-101

MR Barnes et al.
al., Lowering industry firewalls
firewalls:: pre
pre--competitive informatics iniciatives in drug
discovery,, Nature Rev.
discovery
Rev. Drug Discov
Discov.. 2009
2009,, 8, 701;
701; PG Wyatt, The emerging academic drugdrugdiscovery sector.
sector. Future Med
Med.. Chem
Chem.. 2009
2009,, 1, 1013;
1013; R Kneller, The importance of new companies
for drug discovery
discovery:: origins of a decade of new drugs.
drugs. Nature Rev.
Rev. Drug Discov
Discov.. 2010
2010,, 9, 867;
867; AJ
Engl. J.
Stevens et al.
al., The role of public
public--sector research in the discovery of drugs and vaccines
vaccines.. N. Engl.
Med.. 2011
Med
2011,, 364
364,, 535.
535.

Corcovado uma das sete novas


maravilhas do mundo

Copacabana Beach

Sugar Loaf

Copacabana beach view from Sugar Loaf

Rio-Niteri bridge

Sunset at Arpoador Beach

Saquarema

Maracan stadium

Barra da Tijuca beach

Botanic
gardem
Jardim
Botnico