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Parkinson’s Disease: the ABC’s of PD Drug Therapy
Kimberly Mulcahy, PharmD, BCPS
Clinical Pharmacist Buffalo Psychiatric Center NYSOMH
Adjunct Faculty University at Buffalo SoPPS
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Disclosure
• No financial interests or relationships to disclose
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Objectives
• Design a patient specific drug regimen for a patient diagnosed with Parkinson’s Disease (PD)
• Identify medications that can cause drug-induced Parkinsonism and medications that can exacerbate PD
• Evaluate signs/symptoms of PD psychosis and recommend therapy modification, including antipsychotic treatment, to increase patient quality of life
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Epidemiology
• Approx. 1% population >60 years old • 3.5% 85-89 years
• 60,000 new cases per year
• Estimates 1 million in United States / 5 million worldwide
• Prognosis: • Decreased life expectancy
• Current medical treatments do not alter mortality
Ellis J.M., Fell M.J. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1013/j.bmd.2017.07.075
Rizek P, Kumar N, Jog M. CMAJ 2016. DOI: 10.1503/cmaj.151179
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Cause
• Genetic factors (10% of cases) • LRRK2 mutation
• Glucocerebrosidase gene mutation
• Parkin mutation
• Environmental factors • Industrial exposure
• Heavy metals (manganese, lead, copper)
• Pesticides
Ellis J.M., Fell M.J. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1013/j.bmd.2017.07.075
Rizek P, Kumar N, Jog M. CMAJ 2016. DOI: 10.1503/cmaj.151179
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Pathophysiology
Chronic, progressive, neurodegenerative disorder
• Progressive premature death of dopaminergic neurons • Motor symptoms: 30-70% neuron loss in
substantia nigra
• Cognitive dysfunction/mood disorders/impulse control: outside of the basal ganglia or in serotonergic and noradrenergic systems
• Autonomic syndromes: outside of brain – spinal cord, peripheral autonomic nervous system
Ellis J.M., Fell M.J. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1013/j.bmd.2017.07.075
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Pathophysiology
Neurodegenerative disease:
• Abnormal protein aggregates in midbrain, brain stem, and olfactory bulb • Lewy Bodies
• α-synuclein
Ellis J.M., Fell M.J. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1013/j.bmd.2017.07.075
Rizek P, Kumar N, Jog M. CMAJ 2016. DOI: 10.1503/cmaj.151179
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Pathophysiology
• Braak staging of Lewy Body deposition:
Stage Sites Affected Major Symptoms
I Dorsal motor nucleus of vagus nerve and olfactory tract
Constipation Loss of smell
II Locus coeruleus & subcoeruleus complex Sleep disorder Mood dysfunction
III Substantia nigra Motor symptoms
IV-VI Cortical involvement Dementia Psychosis
Rizek P, Kumar N, Jog M. CMAJ 2016. DOI: 10.1503/cmaj.151179
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Diagnosis
• Neuroimaging: • DaTscan
• MRI
• Transcranial Doppler ultrasonography
• PET
• SPECT
• Biomarkers • α-synuclein in CSF
Rizek P, Kumar N, Jog M. CMAJ 2016. DOI: 10.1503/cmaj.151179
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Diagnosis
• Clinical features and history of symptoms: • Asymmetric motor manifestations
• Resting tremor
• Hypophonia
• Masked facial expression
• Micrographia
• Stiffness/rigidity
• Bradykinesia
• Shuffling gait
• Poor balance
Rizek P, Kumar N, Jog M. CMAJ 2016. DOI: 10.1503/cmaj.151179
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Diagnosis
• Neurologic exam: • Limb stiffness?
• Animated expression?
• Tremor?
• Normal gait? Arm swing present?
• Balance?
• Ease of rising from sitting?
Rizek P, Kumar N, Jog M. CMAJ 2016. DOI: 10.1503/cmaj.151179
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Symptoms
Psychiatric
Depression / anxiety Hallucinations, psychosis, delusions Dementia Cognitive impairment Compulsions/impulsivity
Autonomic
Constipation Urinary urgency/incontinence Orthostasis Sexual dysfunction
Sleep Restless leg syndrome (RLS) Insomnia Daytime somnolence
Sensory Pain Numbness Parathesias
Other
Olfactory impairment / odor identification deficit Dysarthria Hypophonia Diplopia
Ellis J.M., Fell M.J. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1013/j.bmd.2017.07.075
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Early v. Late Symptoms Early Late
Motor
Tremor of hand, jaw, or foot Bradykinesia Decreased facial expression Decreased arm swing or leg dragging Frozen shoulder Stiffness/numbness/pain in limb Difficulty turning in bed Micrographia Soft Voice
Motor fluctuations Choreiform dyskinesias Gait freezing Falls
Non-Motor
Constipation (approx. 30%) REM sleep behavior disorder Depression Olfactory impairment (up to 97%)
Dysphagia Neuropsychiatric symptoms Dementia Autonomic disturbances Seborrheic dermatitis
Rizek P, Kumar N, Jog M. CMAJ 2016. DOI: 10.1503/cmaj.151179
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Treatment
• Goals: • Increase dopamine (DA) in the striatum
• Challenges: • Slow progression (targeting in clinical trials)
• Symptom relief v. modifying disease progression
• Multiple medication adjustments and adjunctive treatments required
Ellis J.M., Fell M.J. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1013/j.bmd.2017.07.075 Rizek P, Kumar N, Jog M. CMAJ 2016. DOI: 10.1503/cmaj.151179 National Institute for Health and Clinical Excellence (2017) Pharkinson’s Disease in adults. NICE Guideline
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Available Treatment Options Medications Mechanisms of Action
DA precursors Levodopa (L-dopa) Immediate precursor of DA
DA agonists
Apomorphine Bromocriptine Ropinirole Pramipexole Rotigotine
Stimulate DA receptors in the brain
MAO-B inhibitors Selegiline Rasagiline
Inhibits MAO-B which degrades DA
COMT inhibitors Entacapone Tolcapone
Reduces peripheral conversion of L-dopa
Anticholinergics Benztropine Trihexyphenidyl
Reduces cholinergic activity (caused by loss of DA) and reduces tremor
Ellis J.M., Fell M.J. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1013/j.bmd.2017.07.075 National Institute for Health and Clinical Excellence (2017) Pharkinson’s Disease in adults. NICE Guideline
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Treatment Algorithm
Levodopa monotherapy
MAO-B Inhibitors
Dopamine Agonists
National Institute for Health and Clinical Excellence (2017) Pharkinson’s Disease in adults. NICE Guideline
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Adjunctive Treatment
• MAO-B Inhibitors • +/- benefit in “off” time • More effective in earlier “wearing off” v. later “on and off”
• Dopamine Agonists • More off time reduction • Non-ergot derived*
• COMT inhibitors • Lower risk hallucintaions • Fewer ADE
• Anticholinergics increased risk cognitive impairment, hallucinations, falls, urinary retention
• Apomorphine +/- efficacy, not first line in adjunct
• Amantadine effective for L-dopa dyskinesias
National Institute for Health and Clinical Excellence (2017) Pharkinson’s Disease in adults. NICE Guideline
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Early Onset PD
• Early onset (Young-Onset PD): • <50 years old
• Slower disease progression
• More likely to have levodopa induced dyskinesias • DA agonist, MOA-B inhibitors, anticholinergics first line treatment
Rizek P, Kumar N, Jog M. CMAJ 2016. DOI: 10.1503/cmaj.151179
National Institute for Health and Clinical Excellence (2017) Pharkinson’s Disease in adults. NICE Guideline
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Levodopa
• Precursor to dopamine
• Combination products: • Carbidopa/Levodopa (also available: ODT, controlled release,
extended release, enteral suspension)
• Carbidopa/Levodopa/Entacapone
• Maintenance dose: • 300-1600 mg/day (L-dopa)
National Institute for Health and Clinical Excellence (2017) Pharkinson’s Disease in adults. NICE Guideline
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Levodopa
• “Off” and “On” phenomena • Short t1/2
• Loss of neuronal storage capability
• “On”/Peak-dose dyskinesias • Choreiform movements
• Peak striatal dopamine levels
• Elevated glutamate levels
• “Wearing off” • As PD progresses, duration of action significantly decreases
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Levodopa Management Effect Treatment
End of dose “wearing off” Increase frequency of L-dopa Add either: COMT inhibitor MAO-B inhibitor DA agonist
Delayed “on” (or no on response) L-dopa on empty stomach L-dopa ODT Switch to IR L-dopa (if taking CR) Apomorphine SQ
Freezing/start hesitation Increase L-dopa Add either: MAO-B inhibitor DA agonist Physical therapy
Peak dose dyskinesia Decrease L-dopa doses Add amantadine
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Dopamine Agonists
• Stimulate DA receptors in the brain
• Not as potent as carbidopa/levodopa • Less likely to cause dyskinesias
• Monotherapy or combination therapy • Apomorphine 3-12 mg/day (injection)
• Bromocriptine 15-40 mg/day
• Pramipexole (ER) 1.5-4.5 mg/day
• Ropinirole (XL) 8-24 mg/day
• Rotigotine 2-8 mg/day
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MAO-B Inhibitors
• Block MAO-B enzyme that breaks down levodopa
• Delay need for carbidopa/levodopa if prescribed in early PD
• Maintenance doses: • Rasagiline 0.5-1 mg/day
• Selegiline 5-10 mg/day
• Selegiline ODT 1.25-2.5 mg/day
National Institute for Health and Clinical Excellence (2017) Pharkinson’s Disease in adults. NICE Guideline
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COMT Inhibitors
• No effects on PD if used as monotherapy
• Prolongs effect of levodopa
• Maintenance doses: • Entacapone 200-1600 mg/day
• Tolcapone 300-600 mg/day
National Institute for Health and Clinical Excellence (2017) Pharkinson’s Disease in adults. NICE Guideline
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Other Medications
• Anticholinergics • Benztropine 1-6 mg/day
• Trihexyphenidyl 6015 mg/day
• Amantadine • Tremor in early PD
• Reduce dyskinesias in DA medication
• 200-300 mg/day
National Institute for Health and Clinical Excellence (2017) Pharkinson’s Disease in adults. NICE Guideline
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Non-motor Symptoms
• Concomitant emotional, cognitive, and behavioral features cause significant disability
• Research shifting towards non-motor symptoms of PD: • Depression
• Anxiety
• Apathy
• Dementia
• Psychosis
Zahodne LB, Fernandez HH. Drugs & aging. 2008;25(8):665-682. National Institute for Health and Clinical Excellence (2017) Pharkinson’s Disease in adults. NICE Guideline
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Psychosis
• 20-40% of PD patients
• Hallucinations, delusions, illusions
• PD psychosis v. Schizophrenia / Schizoaffective disorder • Psychosis develops after PD diagnosis
• Primarily paranoid delusions
• Visual hallucinations/sensory disturbances (presence hallucinations) • Evening time
• Worsens over time
Zahodne LB, Fernandez HH. Drugs & aging. 2008;25(8):665-682.
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Psychosis
• PD drugs increase susceptibility to psychosis • Hyperensitization of DA receptors in niagrostriatal pathway due to chronic
stimulation
• Misattributions of internal stimuli
• Dysfunction of limbic structures
• Disease progression and changes in neurochemical processes and structural pathophysiology
Zahodne LB, Fernandez HH. Drugs & aging. 2008;25(8):665-682.
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Psychosis
Brainstem & Sleep
Dysfunction Parkinson’s
Disease Medications
Deep Brain Stimulation
Surgery
Visual Dysfunction
Cortical Pathology
Genetics, Neurochemical Abnormalities
Adapted from: Zahodne LB, Fernandez HH. Drugs & aging. 2008;25(8):665-682.
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Psychosis
• Treatment: • Evaluate for underlying condition
• Reduction of anti-PD drugs
• Reduce/remove medications that can induce/exacerbate psychosis
Fredericks D, et al. Am J Manag Care. 2017 Apr;23(5 Suppl):S83-S92 Zahodne LB, Fernandez HH. Drugs & aging. 2008;25(8):665-682.
Yuan M, et al. Brain and Behavior. 2017;7(6):e00639.
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Psychosis
• Medications that can induce/worsen psychosis: • Tricyclic antidepressants
• Antihistamines
• Anticholinergics
• Amantadine
• DA agonists
• COMT inhibitors
• L-dopa
Zahodne LB, Fernandez HH. Drugs & aging. 2008;25(8):665-682.
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Psychosis
• Treatment: • Evaluate for underlying condition
• Reduction of anti-PD drugs
• Reduce/remove medications that can induce parkinsonism
• Switch levodopa from ER to immediate release
• Add antipsychotic medication • BBW: increased risk of mortality in elderly patients with dementia
• Second generation antipsychotics • Metabolic syndrome
• Orthostatic hypotension
Zahodne LB, Fernandez HH. Drugs & aging. 2008;25(8):665-682. Fredericks D, et al. Am J Manag Care. 2017 Apr;23(5 Suppl):S83-S92
Yuan M, et al. Brain and Behavior. 2017;7(6):e00639.
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Clozapine
• Safety, tolerability, efficacy shown in multiple RCT and open label trials
• Psychosis treatment reached in doses as small as 6.25 mg/day
• Minimal effects on tremor/movement symptoms of PD
• Patients must be enrolled in the REMS program • Agranulocytosis
• Worsened PD symptoms in doses >150 mg/day
Zahodne LB, Fernandez HH. Drugs & aging. 2008;25(8):665-682. Fredericks D, et al. Am J Manag Care. 2017 Apr;23(5 Suppl):S83-S92
Yuan M, et al. Brain and Behavior. 2017;7(6):e00639.
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Quetiapine
• 12.5-25 mg at bedtime • Studies show tolerability up to 200 mg
• Positive effect on sleep architecture
• Minimal effect on worsening motor symptoms
Yuan M, et al. Brain and Behavior. 2017;7(6):e00639.
Zahodne LB, Fernandez HH. Drugs & aging. 2008;25(8):665-682. Fredericks D, et al. Am J Manag Care. 2017 Apr;23(5 Suppl):S83-S92
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Psychosis Treatment Misc.
• Risperidone • Majority open label studies
• Mixed results in efficacy
• Reports of severely worsening motor symptoms
• Ziprasidone • Lacks data in regards to proven efficacy
• Risk of QTc prolongation
• Aripiprazole • Studies with small n
• Significant akathisia reported
Yuan M, et al. Brain and Behavior. 2017;7(6):e00639.
Zahodne LB, Fernandez HH. Drugs & aging. 2008;25(8):665-682. Fredericks D, et al. Am J Manag Care. 2017 Apr;23(5 Suppl):S83-S92
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Pimavanserin
• First FDA approved medication for PD psychosis
• 5-HT2A receptor inverse agonist • No activity on DA receptors like other antipsychotic medications
• Not found to worsen PD motor symptoms
• 17 – 34 mg daily
• Same safety concerns as antipsychotics: • Neuroleptic sensitivity reactions, increased risk of mortality, stroke, and
pulmonary embolism, and accelerated cognitive decline
• Awaiting further post marketing information and longer duration of use
Kianirad Y, Simuni T. Expert Rev Clin Pharmacol. 2017 Aug 18. Cummings J et al. Lancet. 383; 533-540.
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Dementia
• Donepezil • Predominately open label studies • Modest efficacy in symptoms of dementia and psychosis
• Lack of statistical significance in trials
• Galantamine • Additional MOA of acting on nicotinic receptors
• Increases release of dopamine
• Small studies • Improvement in dementia symptoms and QOL
• Worsening of tremor frequently reported
Fredericks D, et al. Am J Manag Care. 2017 Apr;23(5 Suppl):S83-S92 Litvienko IV et al. Neurosci Behav Physiol. 2008 Nov;38(9):937-945 Zahodne LB, Fernandez HH. Drugs & aging. 2008;25(8):665-682.
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Dementia
• Rivastigmine – approved for PD dementia • Dual action: acetylcholinesterase and butyrylcholinesterase inhibitor
• Improves: cognition, attention and executive functions, ADLs, and behavioral symptoms
• 3-12 mg/day
Fredericks D, et al. Am J Manag Care. 2017 Apr;23(5 Suppl):S83-S92 Zahodne LB, Fernandez HH. Drugs & aging. 2008;25(8):665-682.
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Depression
• Underdiagnosed – approx. 50% diagnosed with PD meet criteria for major depressive disorder
• Mixed results with antidepressant therapy: • TCA’s
• Improvement in sleep
• Paroxetine & Venlafaxine • Improvements shown as early as 4 weeks
• Significant improvements and responsiveness on depression and PD rating scales
Kelberman MA, Vazey EM. Curr Pharmacol Rep (2016)2:253.
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Conclusion
• Pharmacotherapy initiation and selection is patient specific • Consider factors such as Young-Onset PD, most troublesome PD symptom,
etc.
• Monitor patient for difficulties with non-motor symptoms as well as motor symptoms • Treatment of psychosis, dementia, and depression improves patient and care
giver quality of life
• Target pharmacotherapy to address patient’s most bothersome symptoms
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Questions?
Parkinson’s Disease: the ABC’s of PD Drug Therapy
Kimberly Mulcahy, Pharm.D., BCPS
Clinical Pharmacist Buffalo Psychiatric Center NYSOMH
Adjunct Faculty University at Buffalo SoPPS
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Coming soon… Drug Company MOA Status
Orotidine (ACR325) / Seridopidine (ACR343) Saniona AB D2 modulators/stabilizers Phase 2
AE04621 / AC04621 Lundbeck D1/D2 agonist Phase 1
PF-06649751 Pfizer D1 agonist Phase 2
IRL-790 Integrated Research Laboratories D2 agonist Phase 1b
LY3154207 Eli Lilly D1 potentiator Phase 1
CLR4001 Clera Inc. D2 agonist Phase 2a
SLS-006 Seelos Therapeutics/Pfizer D2 /D3 partial agonist Phase 3
RP-5063 / RP-5000 Reviva Pharmaceuticals D2 /D3/D4/5HT1A/5HT2A partial agonist, 5HT6/5HT7 antagonist Phase 2
KDT3594 Kissei Pharmaceuticals D2 agonist Phase 1
YKP-10461 SK Biopharmaceuticals/Celerion Reversible MAO-B inhibitor Phase 1
ODM-104 (in combo with l-DOPA) Orion Pharma COMT inhibitor Phase 2
SAGE-217 Sage Therapeutics GABA modulation Phase 2
ODM-106 Orion Pharm GABAB receptor modulator Phase 1
KW-6356 Lundbeck/Kyowoa Hakko Kirin adenosine2A antagonist Phase 2
Tozadenant (sYN-115) Roche/Biotie Therapies adenosine2A antagonist Phase 3
Eltoprazine 5HT1A5HT1B agonist, 5HT2C antagonist Phase 2
Landipirdine (sYN-120) Biotie Therapies 5HT6/5HT2A antagonist Phase 2
Foliglurax (PXT-002331) Prexton Therapeutics Glutamate modulator Phase 2
Ellis J.M., Fell M.J. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1013/j.bmd.2017.07.075
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Appendix A UK Parkinson’s Disease Society Brain Bank for diagnosing Parkinson’s disease:
• Bradykinesia and at least one of the following: • Rigidity • Resting tremor • Postural instability not caused by primary visual, vestibular, cerebellar or proprioceptive dysfunction
• Exclusion of other causes of parkinsonism
• At least three of the following supportive (prospective) features: • Unilateral onset • Persistent asymmetry primarily affecting the side of onset • Resting tremor (hand, leg or jaw, asymmetric, disappears with action) • Excellent response to levodopa (70-100%) • Progressive disorder • Severe levodopa-induced chorea (dyskinesias) • Levodopa response for five years of more • Clinical course of 10 years or more
Rizek P, Kumar N, Jog M. CMAJ 2016. DOI: 10.1503/cmaj.151179
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Appendix B
• Differentiating between PD and Essential Tremor
PD Essential Tremor
Age >60 y/o Any
Facial Expression Reduced Normal
Family History Positive Positive
Gait Unstable Freezing
Normal
Muscle Tone Weakness, cogwheel rigidity Normal
Tremor Characteristic Resting (pill rolling) Unilateral
Postural Bilateral
Ellis J.M., Fell M.J. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1013/j.bmd.2017.07.075