CHEM E-120Spring 2011

Introduction to Medicinal Chemistry and Pharmacology

Development of Neuronin & Lyrica

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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

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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

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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

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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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Voltage-Gated Calcium 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

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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

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CNS Drug Properties

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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

Gabapentin

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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.

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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]

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Gabapentin - Heteroatoms

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Later SAR investigated1.Binding conformations2.Ring constraints3.Alkyl substituents on the ring4.heteroatoms

Accesses hydrophobic pocket?

Gabapentin

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Gabapentin

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Gabapentin

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Bioorganic & MedicinalChemistry 1999 p715

Bioisosteric Replacement of COOH

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pKa = 8.2 pKa = 8-10

Gabapentin

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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

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R

S

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%.

Pregabalin

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Pregabalin

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After 2 hrs po

Pregabalin

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Suggests entryto brain not bySystem L