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