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