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