en busca del opioide ideal. nuevas moléculas · 2018. 1. 30. · • combinaciones Ø ... gic-1001...
Post on 02-Feb-2021
2 Views
Preview:
TRANSCRIPT
-
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)
-
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
↑ Benefit-Risk relationship = Benefit Risk
= ↓
-
Why investigate in opioids ?
-
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
-
Why investigate in opioids ?
-
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
Why investigate in opioids ?
-
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.
Phase II 47% Phase III 13%
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.
Phase II 44% Phase III 31%
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
-
Why investigate in opioids ?
1.- Fracaso nuevos mecanismos de acción en analgesia
2.- Los agonistas opioides continúan siendo hasta el
momento los mejores analgésicos de que disponemos
-
Why investigate in opioids ?
1.- Fracaso nuevos mecanismos de acción en analgesia
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
-
Why investigate in opioids ?
1.- Fracaso nuevos mecanismos de acción en analgesia
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 1.MOPagonist:Biasedµ-opioidreceptorligands
↑ Benefit-Risk relationship = Benefit Risk
= ↓
-
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
-
Searching for the ideal opioid: Novel Pharmacology 1.MOPagonist:Biasedµ-opioidreceptorligands
PhaseIIIcompleted
Be#ersafetyvs.opioids:reducednausea,vomi7ngand
hypoven7la7on
Oliceridine(TRV130):Biasedµ-opioidagonist
-
Searching for the ideal opioid: Novel Pharmacology
• Mul>targetopioidligands
2.Mul>-mechanis>cligands
7PhaseIIcompleted
Be#ersafetyvs.opioids:reducedrespiratorydepressionandabusepoten7al
Cebranopadol:μ-opioid+NOPagonist
Cebranopadol
Kagoperipheral
GIC-1001
PhaseIIOngoing
Pain&IBS
-
Searching for the ideal opioid: Novel Pharmacology
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,)
5.COMBOs:OPIOIDSAGONISTandOPIOIDSANTAGONIST
Searching for the ideal opioid: OTHER INDICATIONS
-
Searching for the ideal opioid: OTHER INDICATIONS
Phase OIC &/or OINV Depressio
n Neurobehavior
al 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
-
Searching for the ideal opioid: OTHER INDICATIONS
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
Searching for the ideal opioid: OTHER INDICATIONS
-
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
Searching for the ideal opioid: OTHER INDICATIONS
-
Phase
Pain(preven>ng
OIC&/orOINV)
Depression
Buprenorphine/samidorphan III X
5.COMBOs:OPIOIDSAGONISTandOPIOIDSANTAGONIST
Label: Pain (preventing OIC &/or OINV), Depression
Searching for the ideal opioid: OTHER INDICATIONS
-
Searching for the ideal opioid – ANALGESIA - Future Mul>-mechanis>cligands
↑ Benefit-Risk relationship = Benefit Risk
↑ ↓
-
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.
top related