Lead Optimization Latin America (LOLA)

FAPESP-RSC-MMV-DNDi workshop
Frontiers in Science on Neglected Diseases
Recent collaborations with Drugs for Neglected Diseases
initiative-DNDi and with Medicines for Malaria Venture-MMV
in the area of neglected diseases
Luiz Carlos Dias
Institute of Chemistry – UNICAMP
Campinas – SP, BRAZIL
The Lead Optimization Latin America (LOLA)
consortium: collaborative drug discovery for
Neglected Tropical Diseases (NTDs)
Luiz Carlos Dias1; Marco A. Dessoy1, Brian Slafer1, Adriano
Andricopulo2, Dale Kempf3, Brian Brown3, Mira Hinman3,
Yvonne C. Martin3, Simon F. Campbell4, Charles E. Mowbray4
de Química – UNICAMP, Campinas, Brazil
2Laboratório de Química Medicinal e Computacional, Centro de Biotecnologica
Molecular Estrutural– USP, São Paulo, Brazil
3AbbVie Inc., Chicago, USA
4Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland
1Instituto
Lead Optimization Latin America (LOLA)
Origins of leads against T. cruzi
Early leads for new drugs for Chagas disease

Monocyclic series
CH 3
CN
H 3C
N
S
S
O
IC50

TDR30139
= 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
3
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
4
MOA is not CYP51 inhibition

TDR30139 & TDR91219 have promising in vitro activity against T. cruzi

Hit to lead chemistry in progress at University of Campinas

Check for CYP51 inhibition before investing too much effort:
CH3
CH3
CN
CH3
N
S
CH3
O
TDR30139
T. cruzi IC50 = 0.34 µM
CYP51 IC50 > 10 µM

CN
S
N
S
O
TDR91219
T. cruzi IC50 = 0.7 µM
CYP51 IC50 > 10µM
Experiment kindly carried out by collaborators at GSK, Tres Cantos, and Dundee
Drug Discovery Unit
5
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
6
Scaleup
H
N
1) Br
S
F
S
O
Boc
CN
N
N
H
Et 3N, CH 2Cl2 (85%)
HN
2) TsOH-H2O, EtOAc, 55 °C
then 2N NaOH
(96%)
S
BWS036
Et 3N, formaldehyde
AcOH, NaBH(OAc)3
CN
N
H
N
S
CH 2Cl2 (99%)
F
O
LOLA3
S
CN
N
N
H
N
S
F
O
LOLA4
F
CN
+ Cl
N
H
S
MAD997
Et 3N, CH 2Cl2
CN
F
(90%)
O
N
S
O
LOLA67
7
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
N
S
O
OH
O
TDR91228
IC50 = 1.2 M
TDR100612
IC50 = 70 M
monocyclic
CH3
S
CN
CH 3
CN
HN
N
H
N
S
F
H3C
O
LOLA3
IC 50 = 0.31 µM
N
N
S
CH3
bicyclic
CN
H
N
O
LOLA48
IC50 = 7.9 µM
H3C
F
S
TDR95696
IC50 = 2.0 M
S
TDR30139
IC50 = 0.34 M
S
N
O
O
CN
HN
HCl
HO
CN
S
N
F
S
O
LOLA67
IC50 = 0.58 M
8
Summary

Cyanopyridine series






Synthetic chemistry is the key to progress
Encouraging in vitro profiles of lead compounds
Leads scaled up for formulation and in vivo studies
Mouse pk carried out
Applying metabolite ID to guide design
Aim to test leads in a mouse model of Chagas disease soon

Apply medicinal chemistry & drug discovery principles to other new
chemical series from Pfizer and AbbVie

Extend the LOLA consortium


DMPK, in vivo models, more chemistry, safety/toxicology,…
Maintain the excellent, close teamwork
9
Unicamp/MMV
Anti-malarial drug
discovery Project
BRAZIL HETEROCYCLES
Defeating Malaria Together
Furan series: Hits from MMV Malaria Box
In vitro
Cytotoxicty
EC50
MRC5 (µM)
Kinetic
Solubility pH
7.4 (µM)
hERG
% inh at 10
µM
MWT
aLogP
EC50
Pf (nM)
MMV019918
384
3.9
800
3
4
83
MMV020505
311
3.4
875
17
44
48
Series found to have short duration of action in rodents
Sites of variation
Synthetic Pathway
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
Rate of Killing assay - PRR
Compounds have a fast rate of killing
(chloroquine like)
Furan series 2013
•
•
•
•
•
Total of 53 analogs synthesized
Pharmacokinetic properties of series improved
Series stopped due to tight SAR
Novel MOA? Target identification with the Gates Target ID project
Publication planned
16
Acknowledgements
Prof. Luiz C. Dias, 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
17
Acknowledgements
Prof. Luiz C. Dias, Susann Krake, Pablo Martinez
and Maitia Labora
Sergio Wittlin
Mark Wenlock and
Stefan Kavanagh
Sue Charman
Paul Willis, Coline Legrand
and Simon Campbell
18
Acknowledgments
SAVING LIVES!!!