Post on 12-Jan-2016
Modelos de gestao para acelerar a inovacao e a integracao de politicas publicas para doencas que afetam populacoes negligenciadas
Os casos LOLA (DNDi) e Brazil Heterocycles (MMV)
Luiz Carlos Dias Instituto de Quimica – UNICAMP
Campinas – SP, BRASIL
Tropical Diseases
MALARIA:
HELP DEFEAT IT!
Public Institutional DonorsPrivate DonorsPrivate Foundations and Private Individual Donors
www.dndi.org
100 million people at risk in Latin America
Endemic 21 countries in Latin and Central America
8 million infected in Latin America
55.000 new cases per year
Kills more people in region than malaria
GLOBAL VIEW
Approximately 8 million cases, 14,000 deaths per year
430,000 disability-adjusted life years (DALYs) are lost per year
Chagas disease is the leading cause of infectious
cardiomyopathy worldwide
DNDi estimates that less than 1% of the infected people
receive treatment
Chagas Disease
Partnership DNDi and:
LAFEPE – Brazil
Fundacion Mundo Sano And Ministerio Saude Argentina
ELEA produces ABARAX
Lead Optimization Latin America (LOLA)
The Lead Optimization Latin America (LOLA) consortium: collaborative drug discovery for
Neglected Tropical Diseases (NTDs)
Luiz Carlos Dias1, Marco A. Dessoy1, Brian W. Slafer1, Adriano Andricopulo2, Dale Kempf3, Brian Brown3, Mira Hinman3, Yvonne C. Martin3, Charles E. Mowbray4, Simon F. Campbell5
1Instituto de Química – UNICAMP, Campinas, Brazil2Laboratorio de Química Medicinal e Computacional, Centro de Biotecnologia Molecular Estrutural– USP, São Paulo, Brazil3AbbVie Inc., Chicago, USA4Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland5Independent consultant
Origins of leads against T. cruziEarly leads for new drugs for Chagas disease
N
CN
S
HN
O
S
N
F
LOLA4IC50 = 0.03 M (in vitro)
H3C N
CH3
CN
S
TDR30139
IC50 = 0.34 M (in vitro)
O
S
Monocyclic series
TDR screening campaign TDR optimisation project
Bicyclic series
NIH funded screen of the Broad Institute compound collection
Design and Analysis of new targetsCollaborative effort by UNICAMP, AbbVie, Simon Campbell & DNDi
SynthesisUNICAMP, Campinas
Primary ParasitologyUSP São Carlos and LMPH, Antwerp
in vitro ADMEAbbvie, Chicago
Secondary ParasitologySwiss Tropical Institute Formulation – in vivo PK
Wuxi AppTech, Shanghai
Mouse model of Chagas DiseaseLSHTM, London
Early screening cascade & partners
General Synthesis
NH2
S
NC+Me Me
O OMe N
H
Me
CN
S
Et3Nethanol
reflux, 30 min
Schmidt, U.; Kubitzek, H. Chem. Ber. 1960, 93, 1559-1565. TDR30139analogues
thiopyridone
monocyclic cyanopyridines
Me N
Me
CN
S R3
bicyclic cyanopyridines
NH2
S
NC+H Ar
O
N O
Et3N, ethanolreflux, 30 min
then piperidinereflux, 18 h
Boc thiopyridone
NH
N
S
CN
Ar
Boc
N
ArCN
S R3
NR
NIH leadanaloguesAbdel-Wadood, F. K.; Abdel-Monem, M. I.; Fahmy, A. M.; Geies, A. A. J. Chem. Res. 2008, 89-94.
MAD328
IC50 > 100 M
N
N
CH3
H3C S
O
S
Synthesis of TDR30139 derivatives
TDR91228
IC50 = 1.2 M
H3C N
CH3
CN
S
S
OH
TDR100524
IC50 = 26 M
H3C N
CH3
CN
S
O
STDR100612
IC50 = 70 M
H3C N
CH3
CN
O
O
S
TDR30139
IC50 = 0.34 M
H3C N
CH3
CN
SO
S
LOLA67IC50 = 0.58 M
SN
CN
CH3
H3C
O
F
N
HN
S
S
CNHN
O
F
LOLA3IC50 = 0.31 µM
N
N
S
S
CNHN
O
F
LOLA4IC50 = 0.03 µM
N
HN
S
CNHN
OLOLA48
IC50 = 7.9 µM
F
HCl
TDR95696
IC50 = 2.0 M
N
CH3
HO
CN
S
O
S
monocyclic
bicyclic
3-cyanopyridines
• Monocyclic and bicyclic subseries
• > 150 analogues synthesized for LOLA
• Sub-µM against T. Cruzi (in vitro)
• Potency not driven by CYP51 inhibition
• No cytotoxicity issues
• Good stability in human and rat liver microsomes
• Low clearance in human and rat
• T. Cruzi amastigote recovery <100% inhibition (limited by solubility)
• CN, C=O, Pyr, side chain, Me groups aryl ring very important
• Increase solubility
N S
O
CH3
CH3
CN
Property Value
T. Cruzi IC50 = 0.7 µM
CYP51 IC50 > 10 µM
Cytotox MRC-5 cells IC50 > 64 µM
Cytotox PMM IC50 > 64 µM
Clint (human mic.) 11.8 L/hr/kg
Clint (human hep.) 16 L/hr/kg
Clint (rat mic.) 42 L/hr/kg
Clint (rat hep.) 45.7 L/hr/kg
Emax < 100% inhibition
solubility poor
www.mmv.org
Combating malaria with the power of research
Malaria is caused by protozoan parasites of the genus Plasmodium – single-celled organisms that cannot survive outside of their host(s). Malaria is the leading parasitic cause of morbidity and mortality worldwide, especially in developing countries where it has serious economic and social costs.
Endemic
Approximately 219 million cases
584,000 deaths per year (91% in Africa)
33,976,000 disability-adjusted life years (DALYs) are lost per year.
Malaria is worldwide the leading parasitic cause of morbidity and mortality
Malaria burden
N
MeO
HON
Quinine
H
NCl
HNNEt2
Chloroquine
O
O
O O
MeH
H
Me
O
Me
H
Artemisinin
O
O
O O
MeH
H
Me
Me
H
O
O
O
OHArtesunate
ClCl
Cl
OH
NnBu2
Lumefantrine
ACT = Artemisinin- based Combination Therapy:
N
N N
N
N N
Cl Cl
Piperaquine
N
N
ClNH2
H2NPyrimethamine
N N
OMe
OMeHN
SO
O
H2NSulfadoxine
S
H2N NH2
O O
Dapsone
Cl
HN
NH
HN
NH
HN
Proguanil R = HChlorproguanil R = Cl
R
Unicamp/MMV Anti-malarial drug discovery Project
BRAZIL HETEROCYCLES
Defeating Malaria Together
Key Partners for screening
Erythrocyte
IndustryAcademia
P. berghei liver stage assayGNF Novartis/ UCSD, USA
In vitro blood stage activitySwiss TPH, Switzerland
P. cynomolgi hypnozoite assay BPRC, Netherlands
Parasite Reduction Ratein vivo hu-SCID modelGSK Tres Cantos, Spain
Gamete formation assaysImperial College UK
Resistance risk assessmentColumbia University, USA
In vitro DMPKIn silico modelling
In vitro DMPKIn vivo DMPKPhys Chem measurements
NH
O
HN
NH
O
O
2.8A
O NH
HN
OH
3.9A
Val851
Ser854
SolventNH2
NH
HN
OLys802
Specificitypocket
Hinge bond.
PfPI4K / hPI3KSelectivity?
PfPI4K / hPI3KSelectivity?
• Binding:• Hinge binder: 1 of 3
possible bonds utilized• Extending substituents into
the specificity pocket• Selectivity:
• Introduction of substitution to exploit differences between human and plasmodium phosphatidylinositol kinases
• Solubility:• Ligand-site exposed to
solvent can carry solubilizing groups
Pfizer – La Jolla solved and refined the co-crystal structure of MMV085400 with human PIK3a
X-ray / homology model Structural Genomics Consortium
SGC – Toronto
Confidential
Key Results March 2015 – and Plans
• 60 derivatives synthesized• Main strenghts of the series:
• PI4K inhibitor• Activity against resistant field isolates• Activity against liver stage• Transmission blocking activity• Broad kinase selectivity:
No serious flags at this stage
• Main issues:• Metabolic stability of amide• Solubility
• Lowering LogD as strategy to improve other issues• Homology model likely available • Predictive models available from AstraZeneca
Acknowledgements
Brian Brown, Mira Hinman,Yvonne C. Martin, and Dale Kempf
Prof. Adriano Andricopulo, Marco Dessoy and Brian Slafer
James Mills
Manu De RyckerMarcel Kaiser
Prof. Louis Maes, An Matheeussen, Margot Desmet
Charlie Mowbray, Eric ChatelainLeandro Christmann and Simon Campbell
Wen Hua
Alan Brown
Acknowledgements
Susann Krake, Pablo Martinez and Maitia Labora
Sue Charman
Mark Wenlock and Stefan Kavanagh
Sergio Wittlin
Paul Willis, Coline Legrandand Simon Campbell