Pipeline for the Development of Novel Drugs

Ústí nad Labem Ostrava Prague Pardubice Brno

HEALTH ENVIRONMENT BioMed Research UH FVZ UHK Faf LFHK University Hospital HK BioMed Research UH FVZ UHK Faf LFHK Faculty of Military Health Sciences Faculty of Medicine Pharmaceutical Faculty Faculty of Science and Faculty of Informatics and Management UHK

2011 2016 7 researchers / 3.2 FTE 64 researchers / 17 FTE 2 institutes (UHHK, FMHS) 4 institutes (UHHK, FMHS, UHK, IMH) - 19 national projects 2 mil CZK 22 mil CZK 8 articles 62 IF articles 6 patents

OUR GROUP University Hospital Hradec Kralove Biomedical Research Center University of Defense Faculty of Military Health Science Department of Toxicology and Military Pharmacy University of Hradec Kralove Faculty of Science – Department of Chemistry; Department of Biology Faculty of Informatics and Management - Center for Basic and Applied Science National Institute of Mental Health Laboratory of Chemistry - Over 60 people in total

AIMS Basic research (own drug development, medical devices, proteomics as diagnostic) Applied research (service for the clinics and private sector e.g. proteomics, pharmacokinetics od drugs etc.) Education and self-development (pre and postgraduated students, internships, seminars)

INTERNATIONAL COOPERATION Canada USA Brazil Croatia Sweden France Germany Serbia Hungary Korea Singapore India UAE UK Italy Slovakia Over 40 IF papers per year (2013 – 42 IF; 2014 – 46 IF; 2015 – 46 IF; 2016 – 48 IF)

Pipeline

In vitro biologial assessment In vivo assesment, toxicity FIELDS OF EXPERTISE Představení proteomické skupiny Centra Biomedicínského Výzkumu 2) Proteomics 3) Medical devices 1) Drug Development: Chemical synthesis In vitro biologial assessment In vivo assesment, toxicity Pharmacokinetics Pharmacodynamics

DRUG DEVELOPMENT PROCESS In silico methods, organic synthesis Design and Synthesis In-vitro evaluation 1st selection Toxicity Pharmacokinetics 2nd selection In-vivo Candidate „Drug candidate “- recommendation for preclinical trials, commercialization, ip protection Pipeline: reactivators, radioprotectives, vaccine adjuvans, decontamination & desinfection, Alzheimer’s drugs, antitumor drugs

VIRTUAL SCREENING, MOLECULAR MODELING Enzyme known structure (enzym, receptor)- RTG; www.pbd.org docking of drug candidates into the enzyme cavity

Multi-Target Directed Ligands CHEMICAL SYNTHESIS Multi-Target Directed Ligands Alzheimer‘s disease ABAD

PHYSICO-CHEMICAL PROPERTIES Assessment: Solubility log P/log D pKa Metabolites: in vitro prediction BBB prediction: PAMPA assay phospholipid layer (fast) CaCo-2 cell line (more precise) PAMPA assay

IN VITRO SCREENING Efficacy on selected target: Fast Simple Economy Availability: Physico-chemical properties BBB penetration Metabolization Safety: Cytotoxicity evaluation

TOXICITY Acute toxicity (MTD, LD50) Sub-acute toxicity (28 days) Chronic toxicity (90 days) i.m., i.v., i.p., p.o., s.c. administration Mice, rats, pig, guinea pig, dog

PHARMACOKINETICS Assesment of promising candidates Plasma or tissue levels T1/2, bioavalability, clearence Organe distribution Blood-brain barrier penetration

PHARMACODYNAMICS IN VIVO ACETYLCHOLINESTERASE REACTIVATORS (In house) RADIOPROTECTIVES (In house) ANTICANCER DRUGS (Medical faculty UK) ALZHEIMER‘S DISEASE (AS Prague) DECONTAMINATION AND DESINFECTION ADJUVANS (In house, Slovak republic) MEDICAL DEVICES

Patents Derivativesof benzothiazolylurea, preparation and their use - Patent 13.8.2014 (PV 2014-539) 14-merkaptotetradecyl)-trimethylammonium-bromide, as surfactant for gold nanorods - Patent 24. 4. 2015 (PV 2015-274) Quaternary ammonium salt, desinfection mixtures and their use - Patent 30. 10. 2015 (PV 2015-768) Desinfectionmixtures with quaternary ammonium salts - Patent 30. 10. 2015 (PUV 2015-31711)