drug discovery and multifactorial diseases · chemi-/bioluminescence as intracellular excitation...
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100 ANOS. COMPROMISSO COM O FUTURO
Drug discovery and
multifactorial diseases
Fernanda Borges
changing the paradigm to find innovative ligands
CIQUP
CIQUP
Materials
Chemistry & Nanoscience Physical &
Biophysical Chemistry
Medicinal Chemistry
Molecular & Supramolecular
Thermodynamics
Nanostructures & Self-organization
Physical Analytical Chemistry &
Electrochemistry
Research Groups
Thematic Lines
Target
Identification
& Validation
Lead
Generation
&
Optimisation
Pre-Clinical
DevelopmentPh I Ph II & III
Contract Manufacturin
g
Less
developed
academic
expertise
Investment
incongruity
Medicinal Chemistry
Pharmaco-
kinetics
Animal
Testing
Toxicology
Bioequival-
ence
Limited first
in man
studies
Clinical Trials
Data
Management
Central Lab
Biostats
APIs
Formulations
Finished
product
Clinical trial
supplies
Medicinal Chemistry group
Drug DevelopmentDrug Discovery
mg-gram mg-gram kgs-tonnes
Disease
Selection
Target
Ident’n
Lead
Ident’n
Optimise
and select
lead
Safety
studies
Demonstrate
effectiveness
Long
term
safety
Large
clinical
trials
Registration
Rational Drug Design
DiseaseTarget (s)
Lead discoveryLead optimizationADMET studies
One disease one target one drug
Rational Drug Design
One disease one target one drug
One disease multi target one drug
Therapeutic effect
One DiseaseTherapeutic
effect
Drug cocktail A single drug
Neurodegenerative diseases
NeuroOncology
ChemistryScreening
Profiling
(Bio)Informatics
BBB penetrating drug candidates
Discovery of NCE for classic targets
Discovery of NCE for new targets
Multi- and dual-target ligands
Bioavailability and toxicity studies (ADMET)
Delivery systems ( with other CIQUP groups)
Research in MedChem group
Other projects
Chemi-/Bioluminescence as Intracellular Excitation Source for
Photodynamic Therapy of Cancer
Project PTDC/QEQ-QFI/0289/2014
CM Magalhães, J.C.G. Esteves da Silva, L. Pinto da Silva,
ChemPhysChem 2016, DOI: 10.1002/cphc.201600270
Discovery of lead compounds
Molecular and physicochemicalcharacterization
Biological screening
LeadOptimization
Molecular Modelling
Biobased scaffolds
Target(s)
Structure-Activity RelationshipsStructure-Property-Activity Relationships
Looking for the pharmacophore
Disease Research in MedChem group
Tailored chemical adjustments
Improving potency/selectivityImproving of drug-like properties
Molecular Modelling
Research in MedChem group
Hypothalamus
Midbrain
PD
Dopamine
Motorcontrol
Mostlysporadic
Cortex
Hippocampus
AD
Acetylcholine
MemoryCognition
95% sporadic5% inherited
ALZHEIMER’S & PARKINSON’S DISEASEDegenerative loss of specific neuronal groups & NT depletion. Primary cause unknown.
9
Levodopa (SINEMET)
Dopamine agonists
COMT inhibitors
MAO-B inhibitors
Mild/moderate efficacy
Side-effects
Non-Dopaminergic
• Anticholinergic Drugs
• Glutamate Antagonists
Used to delay or slow the symptoms
Basal
ganglia
Our targetMonoaminoxidase-B
Our targetCatechol O-methyltransferase
(R)-(−)-Deprenyl Rasagiline
MAO-B inhibitors in the marketSelective and irreversible inhibitors of MAO-B
Side effects:
Severe headache, tachycardia,
arrhythmia, hallucinations, chorea
Tolcapone Entacapone
COMT inhibitors in the market
tight binding -COMT inhibitors
Severe headache, tachycardia,
arrhythmia, chorea
Tolcapone –BBB permeable
Restricted use
Entacapone –peripheral inhibitor
Low bioavailability-short-acting
Opicapone-peripheral inhibitor
long acting
O
Opicapone
Benzopyran based MAO-B inhibitors
higher inhibitory potency than
(R)-(−)-deprenyl (42- and 25-fold) and rasagiline (123- and 74-fold)
Higher selectivity over MAO-A.F Borges et al, J Med Chem, 2016
non-competitive inhibitor
competitive inhibitor
reversible and selective MAO-B inhibitiors
Benzopyran based MAO-B inhibitors
Compound MWa pIC50 Na cLogPa tPSA (Å2)a HBAa HBDa nrotba LLE Log BB AEI
20 299.71 9.39 21 3.29 59.31 4 1 2 6.10 -0.239 10.29
27 293.32 9.17 22 3.46 59.31 4 1 2 5.71 -0.213 9.64
Rasagiline 171.24 7.30 13 2.10 12.03 1 1 2 5.20 0.280 43.26
(R)-(−)-Deprenyl 187.29 7.77 14 2.64 3.24 1 0 4 5.13 0.492 158.32
CNS+ drugs <450 ___ ___ <5 <60-70 <7 <3 <8 >5 ≥ -1 ___
LLE: ligand-lipophilicity efficiency; Log BB: logarithm of the ratio of the concentration of a drug in the brain and in the blood; AEI: ADMET efficiency index.
. Drug-like properties
0
50
100
150
***
***
**
CTRL
1 uM
10 uM
20 27
MT
T r
ed
ucti
on
(% o
f co
ntr
ol)
Preliminary toxicity studies (in progress)
human neuroblastoma
SH-SY5Y cells
F Borges et al, J Med Chem, 2016
NH2
HOOC
A1
A2A
MAO-Binhibitors
ARligands
O
O
R
R
O
N
R2
R1AChE/BuChEinhibitors
O
O
N
Cinnamic based COMT inhibitors
Borges et al, J Med Chem, 2016
cpmdBBB
Perm.
COMT (nM) TAI (% aggr. Inhib.)
Cu(II) chelation
TOX risk
Liver Brain Metab. Redox Mitotox
CNCAPE +/- 65 3.77 74 Yes - - -
Tolcapone +/- 30 0.91 65 Yes ? - +
Entacapone - 35 3.47 60 Yes ? - -
CNCAPE
Parkinson is a multifactorial disease
NH2
HOOC
Adenosine Receptor Ligands
COST ACTION - CA15135
Multi-target paradigm for innovative ligand identification in the drug discovery process (MuTaLig)
Network
www.mutalig.eu
CanadaChileGermanyIranItalyNetherlandsSpainPortugal UK
Playing dirty
“Forget drugs carefully designed to hit oneparticular target — a better way of treatingcomplex diseases such as cancer may be to aim forseveral targets at once”- Simon Frantz.
NATURE|Vol 437|13 October 2005
“The idea of magic bullets is great, but in practiceit’s probably not going to be the right approachfor complex diseases.” — Bryan Roth
Current Opinion in Structural Biology 2006, 16:127–136