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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
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 ?
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
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
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
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
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.
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.
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