CHEM E-120 Spring 2011 Introduction to Medicinal Chemistry and Pharmacology Development of Neuronin...
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Transcript of CHEM E-120 Spring 2011 Introduction to Medicinal Chemistry and Pharmacology Development of Neuronin...
CHEM E-120Spring 2011
Introduction to Medicinal Chemistry and Pharmacology
Development of Neuronin & Lyrica
1/26/2011
12011 CHEM E-120
Psychiatric Disorders
• Psychosis– Schizophrenia
• Mood– Depression, Anxiety, Bipolar
• Cognitive Function– Alzheimer’s Disease
• Neurodegeneration– Parkinison’s Disease, Alzheimer’s Disease
• Neurobiology Level– Loss of neurons, disruption of neuronal activity, perturbation of neurotransmitter
level’s• Medicinal Chemistry
– drug development for modulation of neurotransmitter levels
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Diagnosis based on psychiatric evaluation by a psychiatrist.No validated, clinical noninvasive physical tests to diagnose mental illness.Psychiatric Diagnosis based on criteria developed by American Psychiatric Association
2011 CHEM E-120
Course Structure
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1. Definition of disorder
2. Neurobiology of disorder
3. Neurochemical entry points for drug development
Protein level – modulation of neurotransmitter levels via interaction of drugs with receptors, ion channels, or enzymes
4. Approved drugs
Mechanism of actionKnown structure-activity-relationshipsPharmacokinetics of the drugs
5. Current medication development
Comments and questions are welcome
2011 CHEM E-120
Gabapentin (Neuronin) & Pregabalin (Lyrica)
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Used in the treatment of epilepsies, pain, mood stabilization - aggressive behavior,anxiety, bipolar disorder.
Both gabapentin and pregabalin bind to a α2-δ protein present in voltage-gated Ca2+ ion channels
Exact mechanisms of action are being discovered
reduces calcium influxreduces glutamate releasechanges amounts of GABA (?)
Gabapentin - Neurontin® Launched by Park-Davis (Pfizer) for epilepsy in 1994Supplemental NDA approved in 2001 for postherpetic neuralgia
2011 CHEM E-120
Pain
Nociceptive Pain
due to a stimulus (hammer, campfire) activation of high threshold sensory pathwaysacting via neurons called nociceptors
Clinical Pain
Inflammatoryvariety of chemical mediators stimulate nociceptors e.g. cytokines (IL-1 and TNF-α)
Neuropathicinitiated or caused by a lesion or dysfunction of the sensory nervous
systemFibromyalgiachronic, widespread pain, fatigue, and heightened pain in response to pressure (allodynia)
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Neuronal Pain Pathway
Dorsal Horn
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Drug Targets/Mediators
Ascending PathwayNMDA/glutamateSubstance P/NK-1Nitric oxide
Descending PathwaySerotoninGABANorepinephrineOpioids
Peripheral TissueNSAIDSProstaglandinsHistamines
sensation of pain
amygdala, NAccdysphoriaunpleasant aspectsof pain
flexor response
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Role of Ion Channels in Pain
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Action potential from site of stimulus to cortex mediated by Na+, K+, and Ca2+
voltage-gated ion channels.
Na+ mediates action potential
Opening of Na+ channels propagates action potential by depolarization of neuron Nav 1.3 is a potential target, is upregulated following injury.
K+ mediates membrane potential
Opening of channel allows K+ flow out polarizing the neuron. GIRK – G-protein-coupled, inward rectifying potassium channel. Activated by opioids, cannabinoids, and α-2 adrenergic agonists
Ca2+ mediates neurotransmitter releasePresynaptic activation releases neuropeptides (substance P) and glutamateCav 2.2 inhibitor - Ziconotide
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Ion Channels
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Cell surface proteins that connect interior of the neuron with extracellular matrix
ligand-gated ion channelsvoltage-gated ion channels
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Dorsal Horn Neuronal Networks – Sites for Analgesics
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sites of action to control pain
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Pain Receptors – Dorsal Horn
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Glu mediates fast transmission
G-protein-coupled, inward rectifying potassium channel
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Synapse
Gap between two neurons (axon-dendrite) across which neurotransmitters diffuse.
Excitory synapseInhibitory synapseModulatory synapse
20 - 40 nm gap - (electrical synapse 3.5 nm)
Presynaptic nerve terminal postsynaptic nerve terminal
Presynaptic and Postsynaptic nerve terminals contain cell surface proteins which interact with neurotransmitters and ions.
Presynaptic neuron transmit the signalPostsynaptic neuron receives a signal
Most drugs elicit a response via interactions at the synapse
2011
Gabapentin
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logP and zwitterionic state are unusual in drugsNo interactions with metabolic cytochrome P450 enzymes, very little side effectsEnters the brain by an amino acid transporter system
GabapentinResearch started in 1973 in a search for GABA mimetics acting at GABA receptors ANDwould cross blood-brain-barrier. Discovered some analogs that prevented seizures in mice.Goedecke (Germany) to Warner-Lambert to Pfizer
Early SAR was in vivo (TSCZ) and focused on methods to increase logP of GABA
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Binding of drugs to proteins
IC50 of a drug is determined from competition experiments where the displacement of a strong binding ligand (usually radioactive) by a drug is measured.
[bou
nd d
rug]
log [drug]
Bmax
Hill-Langmuir Equation
assumes [D] >> [R]
Bmax = [R] receptor sitesB = [DR]
€
[DR] =[R]T[D]KD +[D]
D + R DR
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Lipophilicity - logPLipophilicity can be quantitatively expressed as a partition coefficient.
The partition coefficient, P, is a ratio of the thermodynamic distribution of a solute (drug) between two immiscible phases.
The most commonly used phases are octanol and water at pH 7.0.
[compound]oct
[compound]aq
P =As a wide range of values are possible, the log value is used: logP
For logP < 0 the compound is more soluble in water
For logP > 0 the compound is more “organic” soluble (membrane)
Log P can be experimentally determined by several methods: shake-flask, HPLC
Experimental logP is a function of temperature, pH, concentration, and the type of organic phase used.
logD For compounds that are ionized at pH 7.3. D - the distribution coefficient - is a function of the logP and pKa of a drug.
The two most important molecular properties affecting logP are molecular size and hydrogen bonding.
2011 CHEM E-120
Gabapentin
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Modification of the amine or carboxylic acid decreases activityEffective salt bridge needed? Implies pKa very important
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Physicochemical Properties of Drugs - pKa
For cocaine, pKa = 8.7,
< pH 8.7 protonated form (salt). > pH 8.7 free base readily pass through BBB at pH 7.4 ~ 9% exists as free base
HA
The pKa of ibuprofen = 5.2 at 250CIn the stomach ~ 0.06 is ionized 94% exists as the acidIn the blood following absorption, [A-]/[HA] ~ 158 99% of ibuprofen will exist as a salt.
A-
Cocaine (B) BH+
For basic drugs their pKa refers to the ionization of BH+ where
If pH = pKa then [A-] = [HA]
2011 CHEM E-120
Gabapentin - Heteroatoms
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Later SAR investigated1.Binding conformations2.Ring constraints3.Alkyl substituents on the ring4.heteroatoms
Accesses hydrophobic pocket?
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Pharmacokinetics - AbsorptionOral drugs (enteral) – passage from gastrointestinal tract (low pH) into bloodstream.
Injection (parenteral) – introduced directly into systemic circulationIntravenous, intrathecal (directly into CSF)
Prefer hydrophobic and neutral drugs to pass GI membranes (passive diffusion)Charged drugs (salts) are more water soluble Drug passes from GI tract to liver before entering systemic circulation
first-pass metabolism
Pass from systemic circulation to cerebrospinal fluid (CSF) and brain blood systemthrough BBB. BBB is a hydrophobic environment.
Drug – hydrophilicity for solubility vs hydrophobicity for membrane passage
Bioavailability (F) = Quantity of drug reaching systemic circulationQuantity of drug administered
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Pharmacokinetics - Excretion
Renal excretion – kidneys have large blood flow
filtration or free drug in plasma into glomerulussecretion into proximal tublereabsorption into systemic circulation or urinary excretion
elimination often obeys first-order kinetics
Clearance (volume/time) CL = rate of elimination (metabolism + excretion)[Drug]plasma
Half-life of drug t1/2 = 0.693Vd/clearance in units of time (hrs)
Determines dosage and dosing rateLoading doseMaintenance dose
Pregabalin - Lyrica
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Originally synthesized as activators of glutamic acid decarboxylase. Found to reduceseizures in mice.
(S)-isobutyl-γ-aminobutyric acid dose-dependentlyinhibited the binding of gabapentin to pig brain membranes.
(R) Was 12 fold less active with no antiseizure activity.
PD 0144723, CI-1008, pregabalin,Lyrica® approved for epilepsy (partial seizures), postherpetic neuralgia, GAD (EU) used for anxiety, mood stabilizers (appear to increase GABA levels)
Lyrica
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In the United States, Lyrica is approved for the management of fibromyalgia. Lyrica is also indicated for the management of painful diabetic peripheral neuropathy, postherpetic neuralgia (pain after shingles), and for the adjunctive treatment of partial onset seizures (a type of epilepsy) in adults. Outside of the United States, Lyrica is indicated in adults for the management of peripheral and central neuropathic pain (NeP), treatment of generalized anxiety disorder, and adjunctive therapy for partial seizures with or without secondary generalization.
Apr 29, 2009 - Patients suffering from post-traumatic peripheral nerve pain treated with Lyrica® (pregabalin) capsules CV experienced significantly reduced pain compared to those taking placebo, according to new data presented today at the American Academy of Neurology annual meeting. The data also showed that patients treated with Lyrica reported less pain interference with sleep and were significantly more likely to report feeling better overall at the end of the study compared with placebo.
Lyrica
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The multi-center, double-blind, placebo controlled study of Lyrica in 254 adult patients with post-traumatic peripheral neuropathic pain randomized patients to receive flexible dose Lyrica 150 mg to 600 mg daily for four weeks of dose optimization, followed by fixed dosing for four weeks. The study was conducted at 60 sites across Canada and Europe. The average Lyrica dose was 326 mg daily. Patients had to experience persisting, neuropathic pain for at least three months following a traumatic event such as an accident, surgery, amputation or a nerve injury and have a pain score greater than or equal to 4 on an 11-point scale.
Patients were asked to measure their pain on a scale of zero to 10; the average baseline scores for study participants were 6.0 in the pregabalin group and 6.3 in the placebo group on this 11-point scale. A score of 4.0 to 7.0 is considered moderate pain and a score of greater than 7.0 is considered severe pain.
The primary endpoint was the difference in average self-reported pain score at the study's conclusion between patients treated with Lyrica and placebo. Secondary endpoints included the effects of Lyrica compared to placebo on co-morbid symptoms of post-traumatic peripheral neuropathic pain including anxiety, patients' self-reported pain-related sleep and patients' self-reported overall improvements.
Patients receiving Lyrica had, on average, a pain score that was 0.62 points lower on an 11-point scale compared to placebo. patients receiving Lyrica had an average self-reported weekly pain-related sleep interference score of 2.73/11 measuring how much pain had interfered with sleep during the past 24 hours, compared to 4.13 for placebo.
Pregabalin
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No correlation between binding affinity and System L transport (active transport of amino acids across the blood-brain barrier – LAT1)Helps confirm a α2-δ protein as the target
Pregabalin - SAR
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The ability of an oral dose of test compounds (30 mg/kg) to restore punished drinking behavior (as evidenced by numberof shocks taken) in rats is expressed as the percent reference activity (PRA) compared to a 30 mg/kg dose of pregabalin which is definedas 100%.