en busca del opioide ideal. nuevas moléculas · • combinaciones Ø ... pf-4480682 (gaba a, pde...

En busca del opioide ideal.

Nuevas moléculas

Barcelona, 1 de diciembre de 2017

Luz Romero PhD

Sebastià Videla MD PhD

Guión

EN BUSCA DEL OPIOIDE IDEAL ESTADO ACTUAL DE LA INVESTIGACIÓN EN OPIOIDES

Ø  Analgesia:

•  “Farmacología nueva” •  Combinaciones

Ø  Indicaciones diferentes a analgesia: •  “Farmacología nueva”: Antagonistas opioides •  Combinaciones (antagonistas opioides + otros)

Opioid Receptor Types

Current NC-IUPHAR Recommended Nomenclature (2000)

Previous Nomenclature

(1996)

Presumed Endogenous Ligands Effects

µ, mu, or MOP OP3

β-endorphin (not selective) enkephalins (not selective) endomorphin-1 (tentative) endomorphin-2 (tentative)

Analgesia, sedation, euphoria, vomiting, respiratory depression, constipation, pruritus, anorexia, urinary retention, miosis, physical dependence

δ, delta, or DOP OP1 enkephalins (not selective) β-endorphin (not selective)

Analgesia (without many adverse effect), not well understood

κ, kappa, or KOP OP2 dynorphin A dynorphin B α-neoendorphin

Analgesia, respiratory depression, dysphoria

NOP (ORL-1) OP4 Nociceptin/orphanin FQ (N/OFQ)

Analgesia and morphine tolerance

µ

δ κ

NOPOpioid

Localization of opioid receptors

OPIOIDE →afinidad selectiva por los receptores opioides centrales y

periféricos ⇒ inhiben: 1) la transmisión de la entrada nociceptiva, y

2) la percepción del dolor

Localization of opioid receptors

OTRAS ACCIONES →efectosadversos

Ideal opioid ? Action Receptor

Benefit Pain inhibition µ, δ, κ, NOP

Risk

Addiction µ > κ

Euphoria and sedation µ

Dysphoric and psychotomimetic κ

Physical dependence µ > κ; δ?

Tolerance µ, κ, δ

Respiratory depression µ, δ

Muscle Pain / Stiffness µ

Miosis µ, κ

Nausea, vomiting µ, κ, δ

Gastrointestinal motility µ, δ?

Bladder motility µ

Diuresis: Inhibition Stimulation

µ κ

Bradycardia µ > δ = κ

Hypotension δ = κ > µ

Endocrine actions: Prolactin release GH release ACTH release ADH inhibition LH Inhibition

µ δ > κ µ, κ κ µ, δ

Ideal opioid – ‘holy grail’

Nature. 2016 Sep 8;537(7619):170-171.

↑ Benefit-Risk relationship = Benefit Risk

= ↓

Ideal opioid – ‘holy grail’

Action Receptor

Benefit

Pain inhibition µ, δ, κ, NOP

Risk

Addiction µ > κ

Respiratory depression µ, δ

Nausea, vomiting µ, κ, δ

Constipation µ, δ?

Tolerance µ, κ, δ


= ↓

Why investigate in opioids ?


1.- Fracaso de la investigación clínica en demostrar la eficacia de nuevos mecanismos de acción / nuevas dianas terapéuticas implicados en analgesia

VRs

Gabapentinoids

Calcium Potassium

NE / NA

GABA

Prostanoids

CBs

FAAH

AMPA / K mGluRs

NMDA

ORL-1

Adenosine

NE-uptake

Bradykinin

NNRs ACh

5-HT

PXs

CCK

CGRP

NO

Opioids

GL

Glutamate

COX Sodium NPY

CRFs CC / CXCRs SST Gal

VIP NKs Muscar. ETs

GDNF

BDNF

NGF NTs

HIST

TNF ILs Other CIT

PTH MAPK TLRs GCH H+ sens. ASICs

HCNs

MMPs Other GFs Antisense

BSAEDs

Other AD

PDEs OREs Other TRPs FGF TREK SuGA MC Alpha a.

O. Kinases

Project Selection

σ1

Mechanism of Action H1

Preclinical & Clinical Validation

Product Profile

Potential Competitive Advantages; Value Added

Other b Other a


Discontinued pain drugs between 2009-2014

1.  Bicifadine (NA/5-HT transpoters)

2.  Esreboxetine (NA transporter, Alpha 2)

3.  MoxDuo (morphine + oxycodone)

1.  BVT-115959 (Adenosine A2a) 2.  AZD-2066 (mGluR5) 3.  AZD-2516 (mGluR5) 4.  LY-545694 (Glu Kainate) 5.  PH-797804 (P38 kinase) 6.  PF-4480682 (GABA A, PDE 5) 7.  KHK-6188 (CB2) 8.  Placulumab (TNF alpha) 9.  AZD-1940 (CB1/2) 10.  Ataciguat (Guanylate cyclase) 11.  ADL-5859 (Opioid Delta) 12.  Radiprodil (Glu NMDA) 13.  Sofinicline (Nicotinic alpha4, beta2) 14.  AZD-2423 (Chemokine CCR2) 15.  SC-75416 (COX-2) 16.  ASP-3652 (Undefined) 17.  Indantadol (MAO A/B; Glu NMDA) 18.  Z-160 (Calcium channel N-type)

1.  BL-1021 (Sodium channels)

2.  NCX-1236 (Nitric Oxide)

3.  PF-3557156 (PDE 7A)

4.  SEP-227900 (D-amino-acid oxidase)

5.  SEP-228432 (DA/NA/5-HT transporters)

6.  NSD-644 (DA/NA/5-HT transporters)

7.  SAR-114137 (Cathepsin S/K)

8.  GPI 5693 (Glutamate Carboxypeptidase II)

9.  AZD 6088 (Muscarinic M1)

10.  BI-660848 (Undefined)

11.  SAR-407899 (Rho-kinase)

Phase I 34%

Adapted from: Expert Opin Investig Drugs. 2015;24(12):1631-46.

Phase II 56% Phase III 9%

Sponsor terminated 1 Strategic 4 Unspecified 15 Adverse effects 2 Lack of efficacy/Low efficacy 8 Low efficacy + safety 1 Pharmaceutical characteristics 1

REASON FOR DISCONTINUATION:

32 drugs

Discontinued pain drugs between 2015-2016 Phase I 40%

Source: Integrity, Cortellis, Companies website.


1.   ALKS-7106 (Opioid receptor agonist)

2.   ASP-9226 (Undefined)

3.   LY-2969822 (mGlu2/3 agonist)

4.   PHE-377 (TRPV1 antagonist)

5.  ODM-108 (TRPA1 inhibitor)

6.   BIA-102474 (FAAH inhibitor)

1.   PF-05089771 (Nav1.7 blocker)

2.   PF-489791 (PDE-5 inhibitor)

3.   Senrebotase (Endopeptidase

modulator)

4.   10% lidocaine (vaginal gel) (Na

channel inhibitor)

5.   ASP-8477 (Undefined)

6.  Dexisometheptene (Imidazoline

I1R agonist)

7.   AZD-5213 (H3 receptor antagonist)

1.   Fulranumab (recombinant IgG2

anti-NGF mAb)

2.   Clonidine (topical gel) (Alpha 2

agonist)

Sponsor terminated 0 Strategic 2 Unspecified 7 Adverse effects 1 Lack of efficacy/Low efficacy 4 Low efficacy + safety 1 Pharmaceutical characteristics 0

REASON FOR DISCONTINUATION:

15 drugs

Discontinued opioid drugs between 2010-2016 Phase I 19%

Source: Integrity, Cortellis, Companies website.


1.  AZD-2327 (Anxiety; Depression) 2.  AZD-7268 (Anxiety; Depression) 3.  PF-4856880 (NeP; Pain) 4.  PF-4856881 (Pain; Postherpetic

neuralgia) 5.  Buprenorphine hemiadipate

hydrochloride (oral tablet, formulated with abuse-deterrent naloxone), (Opiate dependence)

6.  Fentanyl (inhaled, liposomal), (Cancer pain; Pain)

7.  LY-2940094 (Alcoholism; Major depressive disorder)

1.  Bevenopran (Constipation)

2.  Fentanyl (inhaled TAIFUN)

(Cancer pain)

3.  Fentanyl (transdermal matrix

patch) (Cancer pain; Pain)

4.  Tramadol (orally

disintegrating tablet)

(Premature ejaculation;

Erectile dysfunction)

5.  MoxDuo (morphine +

oxycodone)

1.  JDTic (Opiate dependence)

2.  KRP-110 (Pruritus)

3.  MT-7716 (Alcoholism)

1.  Tramadol + PDE5 inhibitor

(Premature ejaculation;

Erectile dysfunction)

Discovery 6%

DELTA agonist 4 DELTA antagonist; MU antagonist 1 KAPPA antagonist 1 MU agonist 6 MU agonist; PDE 5 inhibitor 1 MU antagonist 1 NOP agonist 1 NOP antagonist 1

TARGET-BASED ACTIONS 16 drugs


1.- Fracaso nuevos mecanismos de acción en analgesia

2.- Los agonistas opioides continúan siendo hasta el

momento los mejores analgésicos de que disponemos



2.- Agonistas opioides →los mejores analgésicos 3.- Los efectos analgésicos de los opioides son

debidos a la activación del sistema opioide endógeno (SOE) ⇒ principal mecanismo inhibitorio que modula de forma fisiológica la transmisión nociceptiva en mamíferos



2.- Agonistas opioides →los mejores analgésicos 3.- Sistema opioide endógeno 4.-

https://www.google.es/search?q=dolar+dinero&espv=2&biw=1536&bih=716&source=lnms&tbm=isch&sa=X&ved=0ahUKEwjwye-v7pTSAhXDcBoKHcLBBNMQ_AUIBigB#imgrc=854OLB6sp4hFlM.

Opioid Consumption by Countries — ME minus Methadone, mg/capita, 2014 Pain & Policy Studies Group (PPSG) - International Narcotics Control Board (INCB)

https://ppsg.medicine.wisc.edu/chart.

The graph shows the aggregate amount of 6 principal opioids countries consumed in morphine equivalence as it relates to their Human Development Index score

Fentanyl

Hydromorphone

Morphine

Oxycodone

Pethidine

Opioid Consumption in Spain

Consumo extrahospitalario - Sistema Nacional de Salud

Source: QuintilesIMS, Disease Insights, Chronic Pain, Oct 2016

Oxycodone Consumption

Launched drugs acting on opioid receptors

Source: Integrity, Cortellis.

Guión

EN BUSCA DEL OPIOIDE IDEAL ESTADO ACTUAL DE LA INVESTIGACIÓN EN OPIOIDES

Ø  Analgesia:

•  “Farmacología nueva” •  Combinaciones

Ø  Indicaciones diferentes a analgesia: •  “Farmacología nueva”: Antagonistas opioides •  Combinaciones (antagonistas opioides + otros)

Searching for the ideal opioid - ANALGESIA

1.MOPagonist:Biasedµ-opioidreceptorligands

2.Mul>-mechanis>cligands

3.KOP/NOPagonist

2.COMBOs:OPIOIDSAGONISTandOPIOIDSANTAGONIST

1.COMBOs:OPIOIDSandothers(NSAIDs,benzodiazepines)

Novelpharmacology:

Combina>ons:

3.COMBOs:OPIOIDSANTAGONISTandOTHERS

Searching for the ideal opioid: Novel Pharmacology 1.MOPagonist:Biasedµ-opioidreceptorligands

Intracellular changes occurring following the binding of an opioid agonist to a G-protein coupled opioid receptor

ReducedneurotransmiTerrelease

7-transmembraneG-proteincoupledreceptor

Rev Pain. 2008 Mar;1(2):2-5. / Br J Pain. 2012 Feb;6(1):11-6.



= ↓

Searching for the ideal opioid: Novel Pharmacology

Label: pain

Phase Pain Pruritus IDBS-

D Pulmonary

Hypertension

TRV130 (Oliceridine)

III MUagobiased X

NKTR-181 III MUago,slowbrainentry X

1.MOPagonist:Biasedµ-opioidreceptorligands


PhaseIIIcompleted

Be#ersafetyvs.opioids:reducednausea,vomi7ngand

hypoven7la7on

Oliceridine(TRV130):Biasedµ-opioidagonist


• Mul>targetopioidligands

2.Mul>-mechanis>cligands

7PhaseIIcompleted

Be#ersafetyvs.opioids:reducedrespiratorydepressionandabusepoten7al

Cebranopadol:μ-opioid+NOPagonist

Cebranopadol

Kagoperipheral

GIC-1001

PhaseIIOngoing

Pain&IBS


Label: pain, pruritus, pulmonary hypertension

PhasePain Pruritus IBS-

D Pulmonary

Hypertension

CR285(Difelikefalin) (iv)III(po)III Kagoperipheral X X

3.KOPagonist

PhasePain

(synergy)Pain

(preven=ngOIC&/orOINV)

Anxiety Cough

Tramadol/dexketoprofen Approved X

Hydrocodone/promethazine/acetaminophen

SubmiTed X X

Tramadol.Celecoxib III X

Sufentanil/triazolam II(discount?) X X

Searching for the ideal opioid: combinations 1.COMBOs:OPIOIDSAGONISTandothers(NSAIDs,benzodiazepines)

Label: Pain (synergy), Pain (preventing OIC &/or OINV), Anxiety, Cough

Phase

Pain(preven>ng

OIC&/orOINV)

Depression

Oxycodone/naltrexone Approved X

Searching for the ideal opioid: combinations 2.COMBOs:OPIOIDSAGONISTandOPIOIDSANTAGONIST

Label: Pain (preventing OIC &/or OINV), Depression

3.COMBOs:OPIOIDSANTAGONISTandothers

Label: Pain

Phase Pain

Naltrexone/clonidine III X

1.Antagonist:MOP/KOP/NOP

Otherindica>ons(≠analgesia):

2.COMBOs:OPIOIDSANTAGONISTandothers

3.KOP/NOPagonist

4.COMBOs:OPIOIDSAGONISTandothers(NSAIDs,benzodiazepines,)


Searching for the ideal opioid: OTHER INDICATIONS


Phase OIC &/or OINV

Depression

Neurobehavioral disorder

Naldemedine

Submitted MUantagoperipheral X

Axelopran II MUantagoperipheral X

CERC-501 II Kantago X

BTRX-246040 II ORL1antago X

1.Antagonist:MOP/KOP/NOP

Label: OIC, OINV, Depression, Neurobehavioral disorder


Phase Schizophrenia CharcotMarieToothtype1

Samidorphan/olanzapine III X

Naltrexone/Baclofen/sorbitol III X

2.COMBOs:OPIOIDSANTAGONISTandOTHERS

Label: Schizophrenia, Charcot Marie Tooth type 1

Label: pain, pruritus, pulmonary hypertension

Phase Pain Pruritus IBS-D Pulmonary

Hypertension

Difelikefalin III Kagoperipheral X X

Asimadoline II Kagoperipheral X X

SER-100 II ORL1partago X

3.KOP/NOPagonist


PhasePain

(synergy)Pain

(preven=ngOIC&/orOINV)

Anxiety Cough

Hydrocodone/guaifenesin SubmiTed X

4.COMBOs:OPIOIDSAGONISTandothers(NSAIDs,benzodiazepines,)

Label: Pain (synergy), Pain (preventing OIC &/or OINV), Anxiety, Cough


Phase

Pain(preven>ng

OIC&/orOINV)

Depression

Buprenorphine/samidorphan III X


Label: Pain (preventing OIC &/or OINV), Depression


Searching for the ideal opioid – ANALGESIA - Future Mul>-mechanis>cligands


↑ ↓

Searching for the ideal opioid – ANALGESIA - Future MutantsReceptorsastherapeu>cagent

The generation of the MORS196A knock-in mouse line supported our initial hypothesis that activation of the mutant receptor with antagonist could produce antinociceptive responses with minimal chronic side effects.

Searching for the ideal opioid – ANALGESIA - Future Mutantsreceptorsastherapeu>cagent

In 1680, Thomas Sydenham: “Among the remedies which it has pleased almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium”

Thomas Sydenham (10-09-1624, † 29-12-1689), médico inglés “Láudano de Sydenham“: Preparación farmacéutica compuesta de opio, azafrán, vino blanco y otras sustancias que se utilizaba como analgésico.

en busca del opioide ideal. nuevas moléculas · • combinaciones Ø ... pf-4480682 (gaba a, pde...

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