Harvard University Extension School CHEM E-120 Chantix TM Varenicline Tartrate.

Harvard University Extension SchoolCHEM E-120

ChantixTM

Varenicline Tartrate

NH

N

N

Substance Abuse

Substance abuse is a worldwide problem costing an estimated $181 billion in the USA alone .

22.6 million persons in the USA aged 12 or older in 2006 were classified with substance dependence or abuse (DSM-IV criteria) in the past year (9.2 percent of the national population)

15.6 million were dependent on or abused alcohol alone3.2 million were classified with dependence on or abuse of both alcohol and illicit drugs3.8 million were dependent on or abused drugs but not alcohol

“a chronic, often relapsing brain disease that causes compulsive drug seeking and use despite harmful consequences to the individual that is addicted and those around them” (NIDA Info Facts 9/2007)

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Stages of Addiction1. Acute reinforcement/social drug taking/Impulsive use

2. Escalating/Compulsive use (e.g. binge drinking)

3. Dependence: Use of a substance despite having clinically significant substance related problems. Discontinuation of the drug causes withdrawal symptoms and the person compulsively takes the drug. Physiological tolerance to the drug can develop

4. Withdrawal: abrupt discontinuation or reduction in the use of a substance

5. Protracted AbstinenceRelapse to the compulsive stage (craving)Withdrawal symptoms are one of the causes of compulsive drug-taking

behavior and short-term relapse.

6. Recovery

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Neurobiology of Addiction 2006, p. 3

Drugs of Abuse

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Long-term neurobiological and neuroanatomical changes.

Main Effect of the drug (directly or indirectly) is upon the mesolimbic dopamine system of the brain with modulation of dopamine transmission and levels

Nature Neuroscience, 2005, 8, 1445

Cocaine Indirect dopamine agonist via inhibition of DAT and promotion of DA release

Amphetamine Indirect dopamine agonist via release of DA mediated via theMethamphetamine DA transporter Opioids Mu opioid agonist Tetrahydrocannabinol CB1 and CB2 agonist Ethanol Positive GABAergic modulator Nicotine nAchR agonist

Substance Abuse – Neurocircuitry of Reward System

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Substance Abuse - Neurocircuitry

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European Neuropsychopharmacology (2007) 17, 377–393

Substance Abuse - Neurotransmitters

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GABA inhibits DA releaseAgonists inhibit GABA releaseInc DA release

Amphetamine transportedInto neuronINC DA RELEASE

Chantix

Goal: develop a compound that would blunt the craving and withdrawal of nicotinebut without the abuse liability.

First evidence:

a. Nicotine replacement therapy (NRT) where the agonist nicotine is supplied via a transdermal patch can reduce craving and withdrawal.b. The nonselective nAchR antagonist mecamylamine reduces consumption.c. A combination of the two drugs (agonist + antagonist) achieved higher abstinence rates than NRT.

Problem is: two drugs, two pharmacokinetic profiles.

Second evidence:

Mu opioid partial agonist buprenorphine reduces opioid dependence.

A partial agonist approach could be therapeutically valid

Chantix - Partial Agonist Theory

Need a drug with high binding affinityand brain penetration (Ceff – free brain levels) to compete with nicotine

When not smoking partial agonist canhave a mild nicotine-like effect and relievecraving. Increasing the dose (abuse) causesno further effect.

CHEM E-120 10

Nicotinic ACh Receptors

CNS - 5 transmembrane proteins that are composed of and/or subunits. Each subunit contains 4 segments.

Related in structure and sequence to GABA, glycine, 5HT3 receptors

2-10 subunit that binds acetylcholine2-4

42 subunit predominates in the CNS – nicotine Ki = 0.95 nM34 antagonism addiction medication?(4)2 (4)3 agonist inc Na+ and K+ permeability(7)5 agonist inc Ca2+ permeability (agonist- cognition, ADHD)

Function at presynaptic locations to regulate release of Glu, D, HT, Ach, and neuropeptides

1/27/2010

NAchR Pharmacophore Model

NAchR Muscarinic

C=O in Ach servesas HBA

Animal Behavioral Models

Impulsive use – Self-administration These methods (operant conditioning) study the positive reinforcing effects of drugs. Drugs that are self-administered by animals (rodent and non-human primates) tend to have a high abuse potential in humans. These studies are performed under various “schedules” to explore different aspects of reinforcement. Fixed ratio (FR) a fixed number of responses are required to obtain the reinforcer. Measurement of the reinforcing strength of a drug. Reinforcing: rate of responding on drug lever > control lever Progressive ratio (PR): the number of responses required are increased to the “break point” ~ greater the break point, greater reinforcing property of the drug.

Animal Behavioral Models

Stimulus Properties of Drugs – Drug Discrimination These methods (operant conditioning) study the ability of an animal to discriminate (tell the difference) between drug and saline. Animal is first trained to associate a reward (food) with a correct lever press

FR20 – when animal presses lever A drug is injected and after 20 presses food is delivered. After training when an animal is given a dose of drug it will chose the drug reinforced lever to be given food.

If the animal is given a different drug and presses the drug reinforced lever then the animal is said to “generalize” to the new drug.

The animal perceives the 2 drugs as being the same.

Discovery Phase

“displace nicotine from its neuronal binding site and reduce the subjective experience of nicotine administration by simultaneously attenuating the dopaminergic response to nicotine”

Examined the biological properties of known nicotinic drugs in:

1. drug discrimination2. self-administration3. ex vivo dopamine release – administer drug to animal, sacrifice and measure DA and/or metabolite levels in appropriate levels of brain.

Cytisine – Ki = 0.17 nM at α4β2 but 56% of nicotine response

Eastern European plant derived natural productInitial cost $30,000/kg – Anticipated 13-18 kg/acre (43,560 ft2)for $150/kg.

Able to get locally 5.5 gm of pure material from 64 kg plant material

N

HN

O

Discovery Phase

Cytisine physical properties:very hydrophilic with logP = 0.01 and logD7.4 = -0.2 (measuring the P of salt)brain-to-plasma (B/P) ratio = 0.1CSF-to-free-plasma ratio = 0.27mw = 190tPSA = 32.34

modify ringWhat is easily chemically modified?modify N – decrease in binding affinity

EC50 = 95 nM vs 9 μM (cytisine)log D = 0.35B/P = 1.4partial agonist with ED50 = 0.032 mg/kgantagonist with ED50 = 0.179 mg/kgsubstituted for nicotineinhibited nicotine self-administrationGenetic toxicity (Ames Test?)

N

HN

O

N

HN

O

Br

Discovery Phase

Work off of 3-pointpharmacophore

cation center

HBApolarizinggroup

synthesis of cytisine w/o the polarizable N and HBA C=O, prepared 100 compds/18 months

Is HBA C=O important?Some other electroniceffect more important?

N

HN

O

Discovery Phase

Explored other heterocycles but none proved useful. (Figure 8)

However: from morphine literature

Brilliant!!!!

“Clearly the change in N position in proceeding from 52 to 53 manifests itself by an almosttotal loss of anti-nociceptive activity and a marked increase in toxicity”

Nicotine and cytisine are toxic – compds 50 to 53 structurally similar to cytisineCould 53 bind to 42 ?????

Lead Optimization

Ki 42 = 0.17 nM 34 nM 20 nM MOR > 2 μM% response of nicotine = 56% 0 (antagonist)

NH

N

HN

O HN

HN

HN

Lead Optimization

SAR to date lead them to rethink role of H-bonding in binding of the compounds to α4β2.

receptor π-electron – sp2 drug interaction

Do not need the C=O, go to heteroaromatic ring systems containing heteroatoms

NH NO2

NO2

H2NH NH2

NH2

O

O

R

R

NH

N

N

Development of varenicline (var en' i kleen)

Development of the Drugagonist

partialagonist

antagonistof nicotine

Screening Strategy

Screening Strategy

Chantix

log P = 1.1pKa = 9.9logD7.4 = -0.28mw=211B/P (rat) = 3.5<20% plasma protein binding – freely availiable90% of drug excreted unmetabolizedno CYP450 interactiont1/2 = 24 hourssteady-state levels achieved in 4 days

Phase 2 – 1 mg once per day (QD)0.5 mg twice per day (BID) 1 mg BID best1.0 mg twice per day (BID)

Phase 3 – after 12 week period 44% 4-week abstinence (30% Bupropion, 18% placebo)after 1 year 22.4% 15.4% 9.3%

Chantix

Some people have had changes in behavior, hostility, agitation, depressed mood, and suicidal thoughts (thinking about harming or killing oneself or planning or trying to do so) while taking varenicline. The role of varenicline in causing these mood changes is unclear since people who quit smoking with or without medication may experience changes in their mental health due to nicotine withdrawal. However, some of these symptoms occurred in people who were taking varenicline and continued to smoke. Some people had these symptoms when they began taking varenicline, and others developed them after several weeks of treatment or after stopping varenicline. These symptoms have occurred in people without a history of mental illness and have worsened in people who already had a mental illness. Tell your doctor if you have or have ever had depression, bipolar disorder (mood that changes from depressed to abnormally excited), schizophrenia (a mental illness that causes disturbed or unusual thinking, loss of interest in life, and strong or inappropriate emotions), or other mental illnesses.

http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000351/