Central Nervous System Drug Design. MacMillan Group Meeting Stefan McCarver November 8 th, 2017
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1 Central ervous System Drug Design MacMillan Group eting Stefan McCarver ovember 8 th, 2017
2 Why is Central ervous System Drug Discovery Important? eurodegenerative Disease Almost 6 million Americans suffer from either Alzheimer s or Parkinson s There is a greater than 50% chance of dementia by age 90 Despite the size of this societal burden, no effective treatments exist! Cummings, J.; Lee, G.; Mortsdorf, T.; Ritter, A.; Zhong, K. Alzheimer s & Dementia 2017, 3,
3 β-amyloid Hypothesis in Alzheimer s Disease Karran, E.; rcken, M.; De Strooper, B. at. Rev. Drug Discov. 2011, 10, 698. Shih, H-P.; Zhang, X.; Aronov, A. M. at. Rev. Drug Discov. 2017
4 β-amyloid Hypothesis in Alzheimer s Disease Karran, E.; rcken, M.; De Strooper, B. at. Rev. Drug Discov. 2011, 10, 698. Shih, H-P.; Zhang, X.; Aronov, A. M. at. Rev. Drug Discov. 2017
5 Why is Central ervous System Drug Discovery Important? Mood Disorders - Depression verall lifetime prevalence rate of 17% (21% of women, 13% of men) Depression is the second leading cause of disability worldwide Responses are often delayed and many patients do not respond to treatment emeroff, C. B.; wens, M. J. ature euroscience 2002, 5,
6 Existing Antidepressant Treatments most best-selling antidepressants have identical biological targets H 2 F Cl Cl C sertraline (Zoloft ) selective serotonin reuptake inhibitor escitalopram (Lexapro ) selective serotonin reuptake inhibitor H H CF 3 S fluoxetine (Prozac ) selective serotonin reuptake inhibitor duloxetine (Cymbalta ) serotonin-norepinephrine reuptake inhibitor
7 Existing Antidepressant Treatments most best-selling antidepressants have identical biological targets H 2 F Cl Cl C sertraline (Zoloft ) selective serotonin reuptake inhibitor escitalopram (Lexapro ) selective serotonin reuptake inhibitor H H CF 3 S fluoxetine (Prozac ) selective serotonin reuptake inhibitor duloxetine (Cymbalta ) serotonin-norepinephrine reuptake inhibitor
8 Existing Antidepressant Treatments serotonin reuptake inhibitor target Coleman, J. A.; Green, E. M.; Gouaux, E. ature 2016, 532, 334.
9 Existing Antidepressant Treatments serotonin reuptake inhibitor target Coleman, J. A.; Green, E. M.; Gouaux, E. ature 2016, 532, 334.
10 Innovation Gap in CS Drug Development investment in CS drug design has decreased rapidly in recent years CS drugs cost more and take longer to bring to market than most other therapies nly 8% of clinical compounds are approved, about half the average success rate Halted drug discovery in pain, depression, and anxiety Halted drug discovery in bipolar disorder, depression, schizophrenia, and anxiety
11 Innovation Gap in CS Drug Development investment in CS drug design has decreased rapidly in recent years CS drugs cost more and take longer to bring to market than most other therapies nly 8% of clinical compounds are approved, about half the average success rate Halted drug discovery in pain, depression, and anxiety Halted drug discovery in bipolar disorder, depression, schizophrenia, and anxiety
12 Designing Therapies for europsychiatric Diseases is Challenging Inadequate Pre-Clinical Models Challenging Target Validation chanisms Poorly Understood
13 Pre-Clinical Models Possess Limited Predictive Value There is growing agreement that there are no animal models of psychiatric disorders such as depression that capture the relevant pathophysiology Pankevich, D. E.; Altevogt, B. M.; Dunlop, J.; Gage, F. H.; Hyman, S. E. euron 2014, 84,
14 Pre-Clinical Models Possess Limited Predictive Value Mobile rat = happy rat Immobile rat = depressed rat Forced Swim Test
15 CS Disease chanisms are ot Well Understood Deep understanding of disease mechanism is difficult to achieve. Human brain biology is incredibly complex Significant differences from animal models Surgical procedures are impossible in most cases Brain disorders are not cell autonomous
16 How Do Molecules Enter and Exit the Brain?
17 The Free Drug Hypothesis I. The free drug concentration at the site of action is responsible for pharmacological activity in vivo II. At steady state in the absence of active transport, free drug concentration is the same on both sides of any biomembrane
18 How Do Molecules Enter and Exit the Brain? Blood-Brain Barrier: Endothelial cells with very tight intracellular junctions Cb,u : unbound brain concentration ISF : interstitial fluid ICF : intracellular fluid A number of transport proteins regulate drug or other molecule concentration in the brain via active transport mechanisms Di, L.; Rong, H.; Feng, B. J. d. Chem. 2013, 56, 2 12.
19 Crossing the Blood-Brain Barrier Most common route: Passive permeation Abbott,. J.; Rönnbäck, L.; Hansson, E. ature Reviews euroscience
20 Crossing the Blood-Brain Barrier Blood-brain barrier permeable S Cl H Do not diffuse across BBB H H H H H H H H H H H Carpenter, T. S.; Kirshner, D. A.; Lau, E. Y.; Wong, S. E.; ilmeter, J. P.; Lightstone, F. C. Biophysical Journal 2014, 107,
21 Crossing the Blood-Brain Barrier Active Transport Abbott,. J.; Rönnbäck, L.; Hansson, E. ature Reviews euroscience
22 Crossing the Blood-Brain Barrier Efflux mechanisms need to be avoided! Abbott,. J.; Rönnbäck, L.; Hansson, E. ature Reviews euroscience
23 P-Glycoprotein diated Efflux P-Glycoprotein Highly expressed at the blood-brain barrier Serves as a molecular pump Very broad substrate specificity Aller, S. G.; Yu, J.; Ward, A.; Weng, Y.; Chittaboina, S.; Zhuo, R.; Harrell, P. M.; Trinh, Y. T.; Zhang, Q.; Urbatsch, I. L.; Chang, G. Science 2009, 323,
24 P-Glycoprotein diated Efflux Aller, S. G.; Yu, J.; Ward, A.; Weng, Y.; Chittaboina, S.; Zhuo, R.; Harrell, P. M.; Trinh, Y. T.; Zhang, Q.; Urbatsch, I. L.; Chang, G. Science 2009, 323,
25 Critical Parameters and How They Are asured 1. Cb,u : unbound brain concentration 2. Kp,uu : unbound brain to plasma ratio 3. Papp : rate of brain permeability 4. ER : efflux ratio
26 Critical Parameters and How They Are asured 1. Cb,u : unbound brain concentration 2. Kp,uu : unbound brain to plasma ratio 3. Papp : rate of brain permeability 4. ER : efflux ratio
27 asurement of Unbound Drug Concentration in the Brain Total Brain Concentration C b Brain Fraction Unbound f u,b C b x f u,b = C u,b Unbound drug concentration is the most important parameter for CS pharmacokinetics. Di, L.; Rong, H.; Feng, B. J. d. Chem. 2013, 56, 2 12.
28 asurement of Unbound Drug Concentration in the Brain In humans, CSF concentration approximates brain concentration when transporters are not involved. C b x f u,b = C u,b Unbound drug concentration is the most important parameter for CS pharmacokinetics. Di, L.; Rong, H.; Feng, B. J. d. Chem. 2013, 56, 2 12.
29 How Do Molecules Enter and Exit the Brain? Blood-Brain Barrier: Endothelial cells with very tight intracellular junctions Cb,u : unbound brain concentration ISF : interstitial fluid ICF : intracellular fluid A number of transport proteins regulate drug or other molecule concentration in the brain via active transport mechanisms Di, L.; Rong, H.; Feng, B. J. d. Chem. 2013, 56, 2 12.
30 Critical Parameters and How They Are asured 1. Cb,u : unbound brain concentration 2. Kp,uu : unbound brain to plasma ratio 3. Papp : rate of brain permeability 4. ER : efflux ratio
31 Blood-Brain Barrier Passive Permeability Donor Well Filter and Lipid mbrane Acceptor Well Parallel Artificial mbrane Permeability Assay The amount of drug in each compartment is measured following an incubation period. Di, L.; Rong, H.; Feng, B. J. d. Chem. 2013, 56, 2 12.
32 Critical Parameters and How They Are asured 1. Cb,u : unbound brain concentration 2. Kp,uu : unbound brain to plasma ratio 3. Papp : rate of brain permeability 4. ER : efflux ratio
33 asuring Efflux Ratio with MDR1-MDCK Culture Cells asure Concentration Madin Darby canine kidney transfection with MDR1 Efflux Ratio (ER) = (compound in apical chamber)/(compound in basal chamber) highly effluxed compounds are prevented from diffusing to the basal chamber Devkar, S. T.; Kandhare, A. D.; Sloley, B. D.; Jagtap, S. D.; Lin, J.; Tam, Y. K.; Katyare, S. S.; Bodhankar, S. L.; Hegde, M. V. J. Adv. Pharm. Technol. Res. 2015, 6, Feng, B.; Mills, J. B.; Davidson, R. E.; Mireles, R. J.; Janiszewski, J. S.; Troutman, M. D.; de Morais, S. M. Drug tab. Dispos. 2008, 36,
34 asuring Receptor ccupancy How can you tell if a drug is reaching its target?
35 asuring Receptor ccupancy vehicle administration tracer administration drug administration tracer administration
36 asuring Receptor ccupancy drug 11 CH 3 H radioligand 5-HT1A receptor occupancy Varnas, K. et. al. J. Pharmacol. Exp. Ther. 2016, 358,
37 asuring Receptor ccupancy Receptor occupancy studies provide the most direct information on drug exposure Cost and time concerns preclude their use for all but the most advanced compounds drug administration tracer administration vehicle administration tracer administration
38 ptimization of Compounds for CS Penetration Lipophilicity ften leads to increased potency Increased off-target activity Polar Surface Area Surrogate measure of hydrogen-bonding and polarity Strong correlation with membrane permeability Hydrogen Bonding Leads to lower passive permeability Increases risk of P-gp efflux pk a Most CS drugs contain at least one basic center High pk a can lead to increased efflux Molecular Flexibility High flexibility can decrease passive permeation Can be improved by IMHB and cyclization Wager, T. T.; Chandrasekaran, R. Y.; Hou, X.; Troutman, M. D.; Verhoest, P. R.; Villalobos, A.; Will, Y. ACS Chem. eurosci. 2010, 1,
39 ptimization of Compounds for CS Penetration analysis of 119 marketed CS drugs and 108 Pfizer CS candidates Wager, T. T.; Chandrasekaran, R. Y.; Hou, X.; Troutman, M. D.; Verhoest, P. R.; Villalobos, A.; Will, Y. ACS Chem. eurosci. 2010, 1,
40 ptimization of Compounds for CS Penetration Lipophilicity ften leads to increased potency Increased off-target activity Polar Surface Area Surrogate measure of hydrogen-bonding and polarity Strong correlation with membrane permeability Hydrogen Bonding Leads to lower passive permeability Increases risk of P-gp efflux pk a Most CS drugs contain at least one basic center High pk a can lead to increased efflux Molecular Flexibility High flexibility can decrease passive permeation Can be improved by IMHB and cyclization Wager, T. T.; Chandrasekaran, R. Y.; Hou, X.; Troutman, M. D.; Verhoest, P. R.; Villalobos, A.; Will, Y. ACS Chem. eurosci. 2010, 1,
41 ptimization of Compounds for CS Penetration LogP = a determination of lipophilicity based on partitioning between octanol and water LogD = a ph dependent counterpart to logp, measured at a specific ph using a buffer Wager, T. T.; Chandrasekaran, R. Y.; Hou, X.; Troutman, M. D.; Verhoest, P. R.; Villalobos, A.; Will, Y. ACS Chem. eurosci. 2010, 1,
42 Increased Lipophilicity Leads to Higher Permeability Passive permeability (Papp) as a function of ph - dependent partition coefficient Waring, M. J. Bioorg. d. Chem. Lett. 2009, 19,
43 Reducing Lipophilicity to Improve Unbound Brain Concentration selective muscarinic M 1 agonist from a GSK high throughput screen receptor is highly expressed in the hippocampus and cerebral cortex potential targets for treatment of cognitive deficits including in Alzheimer s and schizophrenia previous compounds showed some clinical efficacy, discontinued due to side effects Johnson, D. J. et. al. Bioorg. d. Chem. Lett. 2010, 20,
44 Reducing Lipophilicity to Improve Unbound Brain Concentration S C # clogp K p f u,b f u,p C u,b (nm) C u,p (nm) K p,uu % 20% % 40% % 38% Johnson, D. J. et. al. Bioorg. d. Chem. Lett. 2010, 20,
45 ptimization of Compounds for CS Penetration Lipophilicity ften leads to increased potency Increased off-target activity Polar Surface Area Surrogate measure of hydrogen-bonding and polarity Strong correlation with membrane permeability Hydrogen Bonding Leads to lower passive permeability Increases risk of P-gp efflux pk a Most CS drugs contain at least one basic center High pk a can lead to increased efflux Molecular Flexibility High flexibility can decrease passive permeation Can be improved by IMHB and cyclization Wager, T. T.; Chandrasekaran, R. Y.; Hou, X.; Troutman, M. D.; Verhoest, P. R.; Villalobos, A.; Will, Y. ACS Chem. eurosci. 2010, 1,
46 ptimization of Compounds for CS Penetration Polar surface area: surface sum over all polar atoms (,, etc.) including attached hydrogens Typically < 140 Å 2 for cell membrane permeability and < 90 Å 2 for BBB permeability
47 Higher Polar Surface Area Reduces CS Exposure S S H H C S H H 1 3 S H H S H H 2 4 # clogp LogD f u,b PSA (Å 2 ) C u,b K p,uu K p,uu Goldberg, F. W. et. al. J. d. Chem. 2014, 57,
48 ptimization of Compounds for CS Penetration Lipophilicity ften leads to increased potency Increased off-target activity Polar Surface Area Surrogate measure of hydrogen-bonding and polarity Strong correlation with membrane permeability Hydrogen Bonding Leads to lower passive permeability Increases risk of P-gp efflux pk a Most CS drugs contain at least one basic center High pk a can lead to increased efflux Molecular Flexibility High flexibility can decrease passive permeation Can be improved by IMHB and cyclization Wager, T. T.; Chandrasekaran, R. Y.; Hou, X.; Troutman, M. D.; Verhoest, P. R.; Villalobos, A.; Will, Y. ACS Chem. eurosci. 2010, 1,
49 ptimization of Compounds for CS Penetration PDE10A inhibitors for the treatment of schizophrenia (Amgen) regulates camp and cgmp in signaling pathway downstream from dopamine receptors H H H F F H initial HTE hit (IC 50 = 10 nm) after optimization (IC 50 = 5 nm)
50 ptimization of Compounds for CS Penetration PDE10A inhibitors for the treatment of schizophrenia (Amgen) regulates camp and cgmp in signaling pathway downstream from dopamine receptors H H H F F H initial HTE hit (IC 50 = 10 nm) after optimization (IC 50 = 5 nm)
51 Hydrogen Bond Donors Can Lead to P-gp Efflux H H H H H H S H # clogp IC 50 (nm) f u,b HBD C u,b efflux ratio K p,uu Hu, E. et. al. J. d. Chem. 2013, 56,
52 Hydrogen Bond Donors Can Lead to P-gp Efflux H H H H H H S H # clogp IC 50 (nm) f u,b HBD C u,b efflux ratio K p,uu Hu, E. et. al. J. d. Chem. 2013, 56,
53 Intramolecular Hydrogen Bonding Generally Improves PK H H 2 H H 2 ER = 3.1 ER = 1.1 H H H Ph H Ph H H K p = 0.4, MED = 30 mg/kg K p = 6.0, MED = 1 mg/kg
54 ptimization of Compounds for CS Penetration Lipophilicity ften leads to increased potency Increased off-target activity Polar Surface Area Surrogate measure of hydrogen-bonding and polarity Strong correlation with membrane permeability Hydrogen Bonding Leads to lower passive permeability Increases risk of P-gp efflux pk a Most CS drugs contain at least one basic center High pk a can lead to increased efflux Molecular Flexibility High flexibility can decrease passive permeation Can be improved by IMHB and cyclization Wager, T. T.; Chandrasekaran, R. Y.; Hou, X.; Troutman, M. D.; Verhoest, P. R.; Villalobos, A.; Will, Y. ACS Chem. eurosci. 2010, 1,
55 α7 icotinic Acetylcholine Receptor Agonists Target of growing interest for cognitive deficits and negative symptoms in schizophrenia Several α7 nachr agonists have demonstrated efficacy in preclinical models C Lead Compound High Throughput Evaluation α7 EC50 = 1.3 µm good selectivity over 5HT3 receptor McDonald, I. M. et. al. Bioorg. d. Chem. Lett. 2013, 23,
56 α7 icotinic Acetylcholine Receptor Agonists R 2 R 1 R 1 C C H H R 2 H H EC 50 (µm) McDonald, I. M. et. al. Bioorg. d. Chem. Lett. 2013, 23,
57 High pka Can Lead to Reduced CS Exposure H pk a = 10.1 ER = 6.9 K p = <0.02 pk a = 8.1 ER = 1.0 K p = 0.9 Attenuated basicity leads to significantly reduced efflux and good brain/plasma distribution McDonald, I. M. et. al. Bioorg. d. Chem. Lett. 2013, 23,
58 ptimization of Compounds for CS Penetration Lipophilicity ften leads to increased potency Increased off-target activity Polar Surface Area Surrogate measure of hydrogen-bonding and polarity Strong correlation with membrane permeability Hydrogen Bonding Leads to lower passive permeability Increases risk of P-gp efflux pk a Most CS drugs contain at least one basic center High pk a can lead to increased efflux Molecular Flexibility High flexibility can decrease passive permeation Can be improved by IMHB and cyclization Wager, T. T.; Chandrasekaran, R. Y.; Hou, X.; Troutman, M. D.; Verhoest, P. R.; Villalobos, A.; Will, Y. ACS Chem. eurosci. 2010, 1,
59 Rigid Structures are ften More mbrane Permeable F F Cl Cl H H 2 H 2 C crizotinib anaplastic lymphoma kinase inhibitor non-small cell lung carcinoma in some patients, point mutations and cancer metastasis into the brain is observed a compound effective against mutant ALK and CS penetrant was needed Johnson, T. W. et. al. J. d. Chem. 2014, 57,
60 Rigid Structures are ften More mbrane Permeable F H 2 Johnson, T. W. et. al. J. d. Chem. 2014, 57,
61 Rigid Structures are ften More mbrane Permeable F F Cl Cl H H 2 H 2 C crizotinib anaplastic lymphoma kinase inhibitor non-small cell lung carcinoma in some patients, point mutations and cancer metastasis into the brain is observed a compound effective against mutant ALK and CS penetrant was needed Johnson, T. W. et. al. J. d. Chem. 2014, 57,
62 Rigid Structures are ften More mbrane Permeable F F F Cl H 2 Cl 1 H H 2 2 H 2 3 C # K i (nm) RB # PSA (Å 2 ) clogp P app ER CSF/C u,p Johnson, T. W. et. al. J. d. Chem. 2014, 57,
63 Questions?
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