Modelos de gestão para acelerar a inovação e a integração de políticas
públicas para doenças que afetam populações negligenciadas
Os casos LOLA (DNDi) e Brazil Heterocycles (MMV)
Luiz Carlos Dias
Instituto de Química – UNICAMP
Campinas – SP, BRASIL
Tropical Diseases
Public Institutional Donors
Private Donors
Private Foundations and Private Individual Donors
www.dndi.org
Chagas Disease
 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
Partnership DNDi and:
LAFEPE – Brazil
Fundacion Mundo Sano
And Ministerio Saude
Argentina
ELEA produces ABARAX
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, Brazil
2Laboratorio de Química Medicinal e Computacional, Centro de Biotecnologia Molecular
Estrutural– USP, São Paulo, Brazil
3AbbVie Inc., Chicago, USA
4Drugs
for Neglected Diseases initiative (DNDi), Geneva, Switzerland
5Independent
consultant
Lead Optimization Latin America (LOLA)
Origins of leads against T. cruzi
Early leads for new drugs for Chagas disease
Monocyclic series
CH3
CN
H3C
N
S
S
O
TDR30139
IC50 = 0.34 M (in vitro)
TDR screening campaign
TDR optimisation project
Bicyclic series
S
CN
N
N
H
N
S
F
O
IC50
LOLA4
= 0.03 M (in vitr o)
NIH funded screen of the Broad
Institute compound collection
Early screening
cascade & partners
Design and Analysis of new targets
Collaborative effort by UNICAMP,
AbbVie, Simon Campbell & DNDi
Synthesis
UNICAMP, Campinas
Primary Parasitology
USP São Carlos and LMPH, Antwerp
Secondary Parasitology
Swiss Tropical Institute
in vitro ADME
Abbvie, Chicago
Formulation – in vivo PK
Wuxi AppTech, Shanghai
Mouse model of Chagas Disease
LSHTM, London
General Synthesis
monocyclic cyanopyridines
Me
O
S
O
Me
Et3N
ethanol
reflux, 30 min
Me
+
NC
Me
CN
Me
NH2
N
H
S
CN
Me
N
S
R3
thiopyridone
TDR30139
analogues
Schmidt, U.; Kubitzek, H. Chem. Ber. 1960, 93, 1559-1565.
bicyclic cyanopyridines
Ar
O
+
H
Ar
Et 3N, ethanol
reflux, 30 min
S
NC
NH2
Boc
then piperidine
reflux, 18 h
Boc N
O
CN
N
N
H
S
thiopyridone
Abdel-Wadood, F. K.; Abdel-Monem, M. I.; Fahmy, A. M.; Geies, A. A. J. Chem. Res. 2008, 89-94.
NIH lead
analogues
Synthesis of TDR30139 derivatives
CH3
CN
S
CN
N
N
CH 3
S
LOLA4
IC 50 = 0.03 µM
H3C
H
N
F
O
N
CN
S
S
H 3C
O
TDR100612
IC50 = 70 M
monocyclic
CH3
CN
CH 3
CN
N
O
OH
TDR91228
IC50 = 1.2 M
S
HN
N
S
H
N
S
F
H3C
O
LOLA3
IC 50 = 0.31 µM
N
N
S
TDR30139
IC50 = 0.34 M
CH3
CN
H
N
S
O
LOLA48
IC50 = 7.9 µM
H3C
F
N
S
TDR95696
IC50 = 2.0 M
S
bicyclic
N
O
O
CN
HN
HCl
HO
CN
S
F
S
O
LOLA67
IC50 = 0.58 M
CH3
3-cyanopyridines
CN
CH3
• Monocyclic and bicyclic subseries
N
S
O
Property
Value
• > 150 analogues synthesized for LOLA
T. Cruzi
IC50 = 0.7 µM
• Sub-µM against T. Cruzi (in vitro)
CYP51
IC50 > 10 µM
Cytotox MRC-5 cells
IC50 > 64 µM
Cytotox PMM
• No cytotoxicity issues
IC50 > 64 µM
Clint (human mic.)
11.8 L/hr/kg
• Good stability in human and rat liver microsomes
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
• Potency not driven by CYP51 inhibition
• 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
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
ACT = Artemisinin- based Combination Therapy:
Unicamp/MMV
Anti-malarial drug
discovery Project
BRAZIL HETEROCYCLES
Defeating Malaria Together
Key Partners for screening
Academia
Industry
P. cynomolgi hypnozoite assay
BPRC, Netherlands
In vitro DMPK
In silico modelling
P. berghei liver stage assay
GNF Novartis/ UCSD, USA
In vitro DMPK
In vivo DMPK
Phys Chem
measurements
Gamete formation assays
Imperial College UK
In vitro blood stage activity
Swiss TPH, Switzerland
Erythrocyte
Resistance risk assessment
Columbia University, USA
Parasite Reduction Rate
in vivo hu-SCID model
GSK Tres Cantos, Spain
Pfizer – La Jolla solved and refined the co-crystal
structure of MMV085400 with human PIK3a
X-ray / homology model
Structural Genomics Consortium
SGC – Toronto
• 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
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
Confidential
Acknowledgements
Prof. Adriano Andricopulo, Marco Dessoy and Brian Slafer
Prof. Louis Maes, An Matheeussen, Margot Desmet
Brian Brown, Mira Hinman,
Yvonne C. Martin, and Dale Kempf
Marcel Kaiser
Alan Brown
Manu De Rycker
James Mills
Wen Hua
Charlie Mowbray, Eric Chatelain
Leandro Christmann and
Simon Campbell
Acknowledgements
Susann Krake, Pablo Martinez and Maitia Labora
Sergio Wittlin
Mark Wenlock and
Stefan Kavanagh
Sue Charman
Paul Willis, Coline Legrand
and Simon Campbell