new treatment for multiple sclerosis/nuevo tratamiento para la esclerosis múltiple

4
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BRAINco Biopharma Multiple sclerosis Drug Discovery project brochure. Licensing opportunity. Folleto descriptivo del proyecto de búsqueda y desarrollo de fármacos en Esclerosis Múltiple. Oportunidad de licencia.

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Page 1: New treatment for Multiple Sclerosis/Nuevo tratamiento para la Esclerosis Múltiple

Hyp

cygusp

neas

ce

asmododif

 

T

 

 

  

pothesis

PDEs are yclic adenouanosine mpecifically co

cAMP plaeuronal survi

well as in n

PDE7 is eells, as well a

Up-regulatissociated toodel. In omaninergicfferent insult

The control

A

enzymes thosine monomonophosphaontrol cAMP

ays key roleival, growth europrotect

expressed inas in brain.

ion of PDEo neuroinfla

this modec neurons ants.

of cAMP lthe trea

New

PhospMultip

Advanta

Ne

Momo

Thpr

Wbr

hat regulate ophosphate ate (cGM

P levels.

es in neurocone respon

tion and neu

n immune

E7A and PDammation iel, PDE7 nd avoided m

levels by PDatment of n

 

treatmhodiester

ple Sclero

ages:

ew small m

olecules aodels.

hey showroperties,

When oralrain and p

intracellula(cAMP)

P). PDE7

onal functionses, neurite

uroinflamma

and pro-inf

DE7B proteinin a Parkin

inhibitors microglial act

DE7 specifieuroinflam

LICE

ent for rase 7 (PDosis (MS)

molecules

are active

w Neuroanswering

lly admiplasma sup

ar levels ofand cyclic

7 enzymes

ons, such ase outgrowth,ation.

flammatory

ns has beennson disease

protectedtivation after

fic inhibitormmatory as

ENSIN

MultipDE7) inhi

with selec

e in two

oprotectivg the main

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s ,

y

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Anti‐NeuNe

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ple Scleribitors fo

ctive PDE

o well est

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nts a new thiseases, suc

cAMP

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PORTU

rosis r the trea

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tablished

Anti-Inical needs

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tiononis

PDE7 

PDE7 inhibitor

UNITY

atment of

y.

MS anim

nflammat.

els found y.

approach f

AM

s

Y

f

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ory

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for

MP

Page 2: New treatment for Multiple Sclerosis/Nuevo tratamiento para la Esclerosis Múltiple

BAC

The mselecneur

BRAhund

IMBCdevel

BIO

Enzy

IM

N In

as

Neur

BLi

Se

Figmo

*B

 

 

  

CKGROUN

main goal ofctive PDE7 inogenic prope

AINco molecudred compoun

Co020 and lopment. A b

OCHEMICA

ymatic activ

MBCo020 an

No significan

ncubation of strocytes) wi

roprotection

RAINco coipopolysacch

elected comp

gure 1. cAMouse macrophag

BRL50481: refere

ND

f this project inhibitors forerties are als

ules have bends belongin

IMBCo010brief descript

AL AND C

ity:

nd IMBCo01

t effect was

f different Mth BRAINco

n and Neuro

ompounds pharide (LPS)

pounds induc

MP productionge cell line.  

ence PDE7 inhibi

Devel

is the generr the treatmeso pursued.

een specificang to differen

are the mtion of the da

CELL BASE

0 showed an

found on oth

MS relevant co compounds

ogenesis:

protected M) induced da

ced the diffe

n in Figuremousenitrite

itor 

 lopmen

ration, selectent of MS. In

lly designednt chemical f

most advanceata obtained

ED ASSAY

n in vitro PD

her PDEs.

cell types (nes resulted in

MS relevant amage (Fig.2

erentiation o

e 2. Neurope macrophages,e production.

nt Stage

tion and devn addition to

d to interact wfamilies has l

ed compounwith these tw

YS

DE7 inhibitio

euroblastomaan increase

cell types).

f postnatal o

protection in , measured by

e: Cand

velopment ofo an anti-infl

with PDE7. led to the sel

nds out of wo compoun

on activity in

a and macroof cAMP lev

s (macropha

oligodendrocy

CNPase

β-Tub

TH

Figure 3immunocyβ-Tub: neu

idate Id

f low molecuflammatory a

The design alection of two

several molnds is present

the nanomo

ophages cell vels (Fig.1).

ages, astroc

yte precurso

. Neurosphereytochemistry (Curonal marker a

dentific

ular weight, activity, neu

and synthesio PDE7 inhi

lecules selected below.

olar range (I

lines, as we

cytes and m

rs and neuro

e differentiatiCNPase: oligodand TH: dopami

ation

orally availaroprotective

is of more thbitors.

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IC50).

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ospheres (Fig

ion analysed dendrocyte marinergic marker)

able, and

han a

rther

mary

from

g.3).

by rker, ).

Page 3: New treatment for Multiple Sclerosis/Nuevo tratamiento para la Esclerosis Múltiple

 

 

                       

  

                          

ANIMAL MODELS

Two well established MS animal models were used: the gold standard experimental autoimmune encephalomyelitis (EAE) and the Theiler’s virus model.

Clinical Score: Clinical scores were significantly improved in the animals treated with BRAINco molecules at the peak of the disease (Fig.4 and 5).

Tissue analysis:

Immunohistochemical analyses of spinal cord samples from treated animals showed anti-inflammatory and neuroprotective properties of the compounds (Fig.6 and 7).

Anti-inflammation

PHARMACOKINETICS, METABOLISM, AND SAFETY CHARACTERIZATION

Initial PK results after single oral administration showed that selected molecules were present both, in plasma and brain, at levels supporting their biological activity.

The compounds also showed good ADME-tox and security profiles (Genotoxicity, Cardiotoxicity, Metabolism, Off-target effects).

Figure 4. Effect of IMBCo010 on EAE animal model. Figure 5. Effect of IMBCo020 on Theiler´s virus animal model.

Figure 6. Decreased microglia reactivity (Iba-1) on the left anddecreased levels of TNF-α pro-inflammatory cytokine on the right.

Figure 7. Myelin staining on the left and Neurofilament staining(protection from axonal damage) on the right. 

Vehicle

IMBCo020

Vehicle

IMBCo020

Development Stage: Candidate Identification

Neuroprotection 

Page 4: New treatment for Multiple Sclerosis/Nuevo tratamiento para la Esclerosis Múltiple

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