Designing CNS Drugs for Optimal Brain Exposure

Blood-Brain Barrier in Drug Discovery: Optimizing Brain Exposure of CNS Drugs and Minimizing Brain Side Effects for Peripheral Drugs

Volumn , Issue , 2015, Pages 385-424

  Rankovic, Zoran ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

Blood brain barrier (BBB); Brain exposure; CNS drugs; H bonding potential; Lipophilicity; Molecular weights (MWs); Pharmacokinetic (PK) parameters; Polar surface area (PSA)

Indexed keywords

BIOCHEMISTRY; BLOOD; MOLECULAR WEIGHT; MOLECULES; PHARMACOKINETICS; UNCERTAINTY ANALYSIS;

BLOOD-BRAIN BARRIER; CNS DRUGS; H-BONDING; LIPOPHILICITY; POLAR SURFACE AREAS;

IONIZATION POTENTIAL;

EID: 85017374771     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9781118788523.ch18     Document Type: Chapter

References (92)

1. Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat. Rev. Neurosci. 2006; 7:41-53.
2. Pardridge WM. The blood-brain barrier: bottleneck in brain drug development. NeuroRx J. Am. Soc. Exp. Neurother 2005; 2:3-14.
3. Shen DD, Artru AA, Adkison KK. Principles and applicability of CSF sampling for the assessment of CNS drug delivery and pharmacodynamics. Adv. Drug Deliv Rev. 2004; 56:1825-1827.
4. Rankovic Z, Bingham M. Medicinal Chemistry Challenges in CNS Drug Discovery. In: Rankovic Z, Bingham M, Nestler E, Hargreaves R, editors. Drug Discovery for Psychiatric Disorders. London: Royal Society of Chemistry; 2013. p 465-509.
5. Pardridge WM. Blood-brain barrier delivery. Drug Discov Today 2007; 12: 54-61.
6. Cecchelli R, Berezowski V, Lundquist S, Culot M, Renftel M, Dehouck M-P, Fenart L. Modelling of the blood-brain barrier in drug discovery and development. Nat. Rev. Drug Discov. 2007; 6:50-661.
7. Pardridge WM. Log(BB), PS products and in silico models of drug brain penetration. Drug Discov. Today 2004; 9:392-393.
8. Liu X, Chen C. Strategies to optimize brain penetration in drug discovery. Curr. Opin. Drug Discov. Dev. 2005; 8: 505-512.
9. Liu X, Smith BJ, Chen C, Callegari E, Becker SL, Chen X, Cianfrogna J, Doran AC, Doran SD, Gibbs JP, Hosea N, Liu J, Nelson F, Szewc MA, Deusen JV. Use of a physiologically based pharmacokinetic model to study the time to reach brain equilibrium: an experimental analysis of the role of blood-brain barrier permeability, plasma protein binding, and brain tissue binding. J. Pharmacol. Exp. Therapeut. 2005; 313:1254-1262.
10. Maurer TS, Debartolo DB, Tess DA, Scott DO. Relationship between exposure and nonspecific binding of thirty-three central nervous system drugs in mice. Drug Metabol. Dispos. 2005; 33:175-181.
11. Hilgert M, Noldner M, Chatterjee SS, Klein J. KA-672 inhibits rat brain acetylcholinesterase in vitro but not in vivo. Neurosci. Lett. 1999; 263:193-196.
12. Gupta A, Hammarlund-Udenaes M, Chatelain P, Massingham R, Jonsson EN. Stereoselective pharmacokinetics of cetirizine in the guinea pig: role of protein binding. Biopharm. Drug Dispos. 2006; 27: 291-297.
13. Johnson DJ, Forbes IT, Watson SP, Garzya V, Stevenson GI, Walker GR, Mudhar HS, Flynn SJ, Wyman PA, Smith PW, Murkitt GS, Lucas AJ, Mookherjee CR, Watson JM, Gartlon JE, Bradford AM, Brown F. The discovery of a series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles as highly brain penetrant, selective muscarinic M1 agonists. Bioorg. Med. Chem. Lett. 2010; 20:5434-5438.
14. Polli JW, Baughman TM, Humphreys JE, Jordan KH, Mote AL, Salisbury JA, Tippin TK, Serabjit-Singh CJ. P-glycoprotein influences the brain concentrations of cetirizine (Zyrtec), a second-generation non-sedating antihistamine. J. Pharm. Sci. 2003; 92:2082-2089.
15. Simon FER, Simons KJ. H1 antihistamines: current status and future directions. World Allergy Organ J. 2008; 1:145-155.
16. Di L, Rong H, Feng B. Demystifying brain penetration in central nervous system drug discovery. J. Med. Chem. 2013; 56:2-12.
17. Sadiq MW, Borgs A, Okura T, Shimomura K, Kato S, Deguchi Y, Jansson B, Bjoerkman S, Terasaki T, Hammarlundudenaes M. Diphenhydramine active uptake at the blood-brain barrier and its interaction with oxycodone in vitro and in vivo. J. Pharm. Sci. 2011; 100:3912-3923.
18. Kageyama T, Nakamura M, Matsuo A, Yamasaki Y, Takakura Y, Hashida M, Kanai Y, Naito M, Tsuruo T, Minato N, Shimohama S. The 4F2hc/LAT1 complex transports L-DOPA across the blood-brain barrier. Brain Res. 2000; 879:115-121.
19. Doran A, Obach RS, Smith BJ, Hosea NA, Becker S, Callegari E, Chen C, Chen X, Choo E, Cianfrogna J, Cox LM, Gibbs J P, Gibbs MA, Hatch H, Hop CE, Kasman IN, LaPerle J, Liu J, Liu X, Logman M, Maclin D, Nedza FM, Nelson F, Olson E, Rahematpura S, Raunig D, Rogers S, Schmidt K, Spracklin DK, Szewc M, Troutman M, Tseng E, Tu M, Van Deusen JW, Venkatakrishnan K, Walens G, Wang EQ, Wong D, Yasgar AS, Zhang C. The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: evaluation using the MDR1A/1B knockout mouse model. Drug Metab. Dispos. 2005; 33:165-174.
20. Wang X, Ratnaraj N, Patsalos PN. The pharmacokinetic inter-relationship of tiagabine in blood, cerebrospinal fluid and brain extracellular fluid (frontal cortex and hippocampus). Seizure 2004; 13:574-581.
21. Martin I. Prediction of blood-brain barrier penetration: are we missing the point? Drug Discov. Today 2004; 9:161-162.
22. Debruyne D. Clinical pharmacokinetics of fluconazole in superficial and systemic mycoses. Clin. Pharmacokinet. 1997; 33:52-77.
23. Smith DA, Di L, Kerns EH. The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery. Nat. Drug Discov. Rev. 2010; 9:929-939.
24. Reichel A. Addressing central nervous system (CNS) penetration in drug discovery: basics and implications of the evolving new concept. Chem. Biodivers. 2009; 9:2030-2049.
25. Veber DF, Johnson SR, Chen H-Y, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 2002; 45:2615-2623.
26. Giacomini KM, Huang S-M, Tweedie DJ, Benet LZ, Brouwer KLR, Chu X, Dahlin A, Evers R, Fischer V, Hillgren KM, Hoffmaster KA, Ishikawa T, Keppler D, Kim RB, Lee CA, Niemi M, Polli JW, Sugiyama Y, Swaan PW, Ware JA, Wright SH, Yee SW, Zamek-Gliszczynski MJ, Zhang L. Membrane transporters in drug development. Nat. Rev. Drug Discov. 2010; 9:215-236.
27. Hitchcock SA. Structural modifications that alter the P-glycoprotein efflux properties of compounds. J. Med. Chem. 2012; 55:4877-4895.
28. Doan MKM, Humphreys JE, Webster LO, Wring SA, Shampine LJ, Serabjit-Singh CJ, Adkinson KK, Polli JW. Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs. J. Pharmacol. Exp. Therapeut. 2002; 303:1029-1037.
29. Demont EH, Arpino S, Bit RA, Campbell CA, Deeks N, Desai S, Dowell SJ, Gaskin P, Gray JRJ, Harrison LA, Haynes A, Heightman TD, Holmes DS, Humphreys PG, Kumar U, Morse MA, Osborne GJ, Panchal T, Philpott KL, Taylor S, Watson R, Willis R, Witherington J. J. Discovery of a Brain-Penetrant S1P3-Sparing Direct Agonist of the S1P1 and S1P5 Receptors Efficacious at Low Oral Dose. Med. Chem. 2011; 54:6724-6733.
30. Seelig A. A general pattern for substrate recognition by P-glycoprotein. Eur. J. Biochem. 1998; 251:252-261.
31. Gombar VK, Polli JW, Humphreys JE, Wring SA, Serabjit-Singh CS. Predicting P-glycoprotein substrates by a quantitative structure-activity relationship model. J. Pharm. Sci. 2004; 93:957-968.
32. Zhang EY, Phelps MA, Cheng C, Elkins S, Swaan PW. Modeling of active transport systems. Adv. Drug Deliv. Rev. 2002; 54:329-354.
33. Broccatelli F, Carosati E, Neri A, Frosini M, Goracci L, Oprea TI, Cruciani G. A novel approach for predicting P-glycoprotein (ABCB1) inhibition using molecular interaction fields. J. Med. Chem. 2011; 54:1740-1751.
34. Didziapetris R, Japertas P, Avdeef A, Petrauskas A. Classification analysis of P-glycoprotein substrate specificity. J. Drug Target. 2003; 11:391-406.
35. Cunningham CW, Mercer SL, Hassan HE, Traynor JR, Eddington ND, Coop A. Opioids and efflux transporters. Part 2: Pglycoprotein substrate activity of 3-and 6-substituted morphine analogs. J. Med. Chem. 2008; 51:2316-2320.
36. Yuan Y, Li G, He H, Stevens DL, Kozak P, Scoggins KL, Mitra P, Gerk PM, Selley DE, Dewey WL, Zhang Y. Characterization of 6α- and 6β-N-heterocyclic substituted naltrex-amine derivatives as novel leads to development of mu opioid receptor selective antagonists. ACS Chem. Neurosci. 2011; 2:346-351.
37. Kuhn B, Mohr P, Stahl M. Intramolecular hydrogen bonding in medicinal chemistry. J. Med. Chem. 2010; 53:2601-2611.
38. Linnet K, Ejsing TB. A review on the impact of P-glycoprotein on the penetration of drugs into the brain. Focus on psychotropic drugs. Eur. Neuropsychopharmacol. 2008; 18:157-169.
39. Wakenhut F, Allan GA, Fish PV, Fray MJ, Harrison AC, McCoy R, Phillips SC, Ryckmans T, Stobie A, Westbrook D, Westbrook SL, Whitlock GA. N-[(3S)-Pyrrolidin-3-yl]benzamides as novel dual serotonin and noradrenaline reuptake inhibitors: impact of small structural modifications on P-gp recognition and CNS penetration. Bioorg. Med. Chem. Lett. 2009; 19:5078-5081.
40. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug. Deliv. Rev. 1997; 23:3-26.
41. Ghose AK, Herbertz T, Hudkins RL, Dorsey BD, Mallamo JP. Knowledge-based, central nervous system (CNS) lead selection and lead optimization for CNS drug discovery. ACS Chem. Neurosci. 2012; 3:50-68.
42. Wager TT, Hou X, Verhoest PR, Villalobos A. Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties. ACS Chem. Neurosci. 2010; 1:435-439.
43. Wager TT, Chandrasekaran RY, Hou X, Troutman MD, Verhoest PR, Villalobos A, Will Y. Defining desirable central nervous system drug space through the alignment of molecular properties, in vitro ADME, and safety attributes. ACS Chem. Neurosci. 2010; 1:420-434.
44. Waring MJ. Defining optimum lipophilicity and molecular weight ranges for drug candi-dates-molecular weight dependent lower logD limits based on permeability. Bioorg. Med. Chem. Lett. 2009; 19:2844-2851.
45. Gleeson MP. Generation of a set of simple, interpretable ADMET rules of thumb. J. Med. Chem. 2008; 51:817-834.
46. Hitchcock SA, Pennington LD. Structure-brain exposure relationships. J. Med. Chem. 2006; 49:7559-7583.
47. Pajouhesh H, Lenz GR. Medicinal chemical properties of successful central nervous system drugs. NeuroRx 2005; 2:541-553.
48. Leeson PD, Davis AM. Time-related differences in the physical property profiles of oral drugs. J. Med. Chem. 2004; 47:6338-6348.
49. Norinder U, Haeberlein M. Computational approaches to the prediction of the blood-brain distribution. Adv. Drug Deliv. Rev. 2002; 54:291-313.
50. Van de Waterbeemd H, Camenisch G, Folkers G, Chretien JR, Raevsky OA. Estimation of blood-brain barrier crossing of drugs using molecular size and shape, and H-bonding descriptors. J. Drug Target. 1998; 6:151-165.
51. Gratton JA, Abraham MH, Bradbury MW, Chadra HS. Molecular factors influencing drug transfer across the blood-brain barrier. J. Pharm. Pharmacol. 1997; 49:1211-1216.
52. Van de Waterbeemd H, Kansy M. Hydrogen-bonding capacity and brain penetration. Chimia 1992; 46:299-303.
53. Leeson PD, Springthorpe B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nat. Rev. Drug Discov. 2007; 6:881-890.
54. Leo A, Hansch C, Elkins D. Partition coefficients and their uses. Chem. Rev. 1971; 71:525-616.
55. Bergström CAS, Strafford M, Lazorova L, Avdeef A, Luthman K, Artursson P. Absorption classification of oral drugs based on molecular surface properties. J. Med. Chem. 2003; 46:558-570.
56. Tantishaiyakul V. Prediction of Caco-2 cell permeability using partial least square multivariate analysis. Pharmazie 2001; 56:407-411.
57. Martin YC. A bioavailability score. J. Med. Chem. 2005; 48:3164-3170.
58. Egan WJ, Merz Jr KM, Baldwin JJ. Prediction of drug absorption using multivariate statistics. J. Med. Chem. 2000; 43:3867-3877.
59. Smith QR, Takasato Y. Kinetics of amino acid transport at the blood-brain barrier studied using an in situ brain perfusion technique. Ann. NY Acad. Sci. 1986; 481:186-201.
60. Goodwin JT, Clark DE. In silico predictions of blood-brain barrier penetration: considerations to "keep in mind". J. Pharm. Exp. Therapeut. 2005; 315:477-483.
61. Murakami H, Takanaga H, Matsuom H, Ohtani H, Sawada Y. Comparison of blood-brain barrier permeability in mice and rats using in situ brain perfusion technique. Am. J. Physiol. Heart Circ. Physiol. 2000; 279:H1022-1028.
62. Liu X, Tu M, Kelly RS, Chen C, Smith BJ. Development of a computational approach to predict blood-brain barrier permeability. Drug Metabol. Dispos. 2004; 32:132-139.
63. Middleton DS, Andrews M, Glossop P, Gymer G, Jessiman A, Johnson PS, MacKenny M, Pitcher MJ, Rooker T, Stobie A, Tang K, Morgan P. Designing rapid onset selective serotonin re-uptake inhibitors. Part 1: Structure-activity relationships of substituted (1S,4S)-4-(3,4 dichlorophenyl)-N-methyl-1,2,3,4-tetrahydro-1-naphthaleneamine. Bioorg. Med. Chem. Lett. 2006; 16:1434-1439.
64. Smith PW, Wyman PA, Lovell P, Goodacre C, Serafinowska HT, Vong A, Harrington F, Flynn S, Bradley DM, Porter R, Coggon S, Murkitt G, Searle K, Thomas DR, Watson JM, Martin W, Wu Z, Dawson LA. New quinoline NK3 receptor antagonists with CNS activity. Bioorg. Med. Chem. Lett. 2009; 19:837-840.
65. Bürli RW, Luckhurst CA, Aziz O, Matthews KL, Yates D, Kathy, Lyons A, Beconi M, McAllister G, Breccia P, Stott AJ, Penrose SD, Wall M, Lamers M, Leonard P, Müller I, Richardson CM, Jarvis R, Stones L, Hughes S, Wishart G, Haughan AF, O'Connell C, Mead T, McNeil H, Vann J, Mangette J, Maillard M, Beaumont V, Munoz-Sanjuan I, Dominguez C. Design, synthesis, and biological evaluation of potent and selective class IIa histone deacetylase (HDAC) inhibitors as a potential therapy for Huntington's disease. J. Med. Chem. 2013; 56:9934-9954.
66. Österberg T, Norinder U. Prediction of polar surface area and drug transport processes using simple parameters and PLS statistics. J. Chem. Inform. Comput. Sci. 2000; 40:1408-1411.
67. Abraham MH. The factors that influence permeation across the blood-brain barrier. Eur. J. Med. Chem. 2004; 39:235-240.
68. Ahmed M, Briggs MA, Bromidge SM, Buck T, Campbell L, Deeks NJ, Garner A, Gordon L, Hamprecht DW, Holland V, Johnson CN, Medhurst AD, Mitchell DJ, Moss SF, Powles J, Seal JT, Stean TO, Stemp G, Thompson M, Trail B, Upton N, Winborn K, Witty DR. Bicyclic heteroaryl piperazines as selective brain penetrant 5-HT6 receptor antagonists. Bioorg. Med. Chem. Lett. 2005; 15:4867-4871.
69. Hu E, Kunz RK, Chen N, Rumfelt S, Siegmund A, Andrews K, Chmait S, Zhao S, Davis C, Chen H, Lester-Zeiner D, Ma J, Biorn C, Shi J, Porter A, Treanor J, Allen JR. Design, optimization, and biological evaluation of novel keto-benzimidazoles as potent and selective inhibitors of phosphodiesterase 10A (PDE10A). J. Med. Chem. 2013; 56:8781-8792.
70. Ghosh AK, Brindisi M, Tang J. Developing β-secretase inhibitors for treatment of Alzheimer's disease. J. Neurochem. 2012; 120:71-83.
71. Brodney MA, Barreiro G, Ogilvie K, Hajos-Korcsok E, Murray J, Vajdos F, Ambroise C, Christoffersen C, Fisher K, Lanyon L, Liu JH, Nolan CE, Withka JM, Borzilleri KA, Efremov I, Oborski CE, Varghese A, O'Neill BT. Spirocyclic sulfamides as β-secretase 1 (BACE-1) inhibitors for the treatment of Alzheimer's disease: utilization of structure based drug design, watermap, and CNS penetration studies to identify centrally efficacious inhibitors. J. Med. Chem. 2012; 55:9224-9239.
72. Kelder J, Grootenhuis PDJ, Bayada DM, Delbressine LPC, Ploemen J-P. Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs. Pharmaceut. Res. 1999; 16:1514-1519.
73. Clark DE. Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 1. Prediction of intestinal absorption. J. Pharmaceut. Sci. 1999; 88:807-814.
74. Pinnard E, Alanine A, Alberati D, Bender M, Borroni E, Bourdeaux P, Brom V, Burner S, Fischer H, Hainzl D, Halm R, Hauser N, Jolidon S, Lengyel J, Marty H-P, Meyer T, Moreau J-L, Mory R, Narquizian R, Nettekoven M, Norcross RD, Puellmann B, Schmid P, Schmitt S, Stalder H, Wermuth R, Wettstein JG, Zimmerli D. Selective GlyT1inhibitors: discovery of[4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl][5-methanesulfo-nyl-2-((S)-2,2,2-trifluoro-1-methylethoxy)phenyl]methanone (RG1678), a promising novel medicine to treat schizophrenia. J. Med. Chem. 2010; 53:4603-4614.
75. Shengguo S, Adejare A. Fluorinated molecules as drugs and imaging agents in the CNS. Curr. Top. Med. Chem. 2006; 14:1457-1464.
76. McDonald IM, Mate RA, Zusi FC, Huang H, Post-Munson DJ, Ferrante MA, Gallagher L, Bertekap Jr. RL, Knox RJ, Robertson BJ, Harden DG, Morgan DG, Lodge NJ, Dworetzky SI, Olson RE, Macor JE. Discovery of a novel series of quino-lone a7 nicotinic acetylcholine receptor agonists. Bioorg. Med. Chem. Lett. 2013; 23:1684-1688.
77. Lerchner A, Machauer R, Betschart C, Veenstra S, Rueeger H, McCarthy C, Tintelnot-Blomley M, Jaton A-L, Rabe S, Desrayaud S, Enz A, Staufenbiel M, Paganetti P, Rondeau J-M, Neumann U. Macrocyclic BACE-1 inhibitors acutely reduce Aβ in brain after po application. Bioorg. Med. Chem. Lett. 2010; 20:603-607.
78. Rampe D, Wible B, Brown AM, Dage RC. Effects of terfenadine and its metabolites on a delayed rectifier K1 channel cloned from human heart. Mol. Pharmacol. 1993; 44:1240-1245.
79. Doan MKM, Wring SA, Shampine LJ, Jordan KH, Bishop JP, Kratz J, Yang E, Serabjit-Singh CJ, Adkison KK, Polli JW. Steady-state brain concentrations of antihistamines in rats: interplay of membrane permeability, P-glycoprotein efflux and plasma protein binding. Pharmacology 2004; 72:92-98.
80. Zhao R, Kalvass JC, Yanni SB, Bridges AS, Pollack GM. Fexofenadine brain exposure and the influence of blood-brain barrier P-glycoprotein after fexofenadine and terfenadine administration. Drug Metabol. Dispos. 2009; 37:529-535.
81. Mihalic JT, Fan F, Chen X, Chen X, Fu Y, Motani A, Liang L, Lindstrom M, Tang L, Chen L-L, Jaen J, Dai K, Li L. Discovery of a novel melanin concentrating hormone receptor 1 (MCHR1) antagonist with reduced hERG inhibition. Bioorg. Med. Chem. Lett. 2012; 22:3781-3785.
82. Hogberg T, Frimurer TM, Sasmal PK. Melanin concentrating hormone receptor 1 (MCHR1) antagonists-still a viable approach for obesity treatment? Bioorg. Med. Chem. Lett. 2012; 22:6039-6047.
83. Jamieson C, Moir EM, Rankovic Z, Wishart G. Medicinal chemistry of hERG optimizations: Highlights and hang-ups. J. Med. Chem. 2006; 49:5029-5050.
84. Gianotti M, Botta M, Brough S, Carletti R, Castiglioni E, Corti C, Dal-Cin M, Fratte SD, Korajac D, Lovric M, Merlo G, Mesic M, Pavone F, Piccoli L, Rast S, Roscic M, Sava A, Smehil M, Stasi L, Togninelli A, Wigglesworth MJ. Novel spirotetracyclic zwitterionic dual H1/5-HT2A receptor antagonists for the treatment of sleep disorders. J. Med. Chem. 2010; 53:7778-7795.
85. Levin VA. Relationship of octanol/water partition coefficients to rat brain capillary permeability. J. Med. Chem. 1980; 23: 682-684.
86. Hopkins AL, Groom CR, Alex A. Ligand efficiency: a useful metric for lead selection. Drug Discov. Today 2004; 9:430-431.
87. Verhoest PR, Sawant-Basak A, Parikh V, Hayward M, Kauffman GW, Paradis V, McHardy SF, McLean S, Grimwood S, Schmidt AW, Vanase-Frawley M, Freeman J, Van Deusen J, Cox L, Wong D, Liras S. Design and discovery of a selective small molecule kappa opioid antagonist (2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl) methyl)propan-1-amine, PF-4455242). J. Med. Chem. 2011; 54:5868-5877.
88. Bromidge SM, Brown AM, Clarke SE, Dodgson K, Gager T, Grassam HL, Jeffrey PM, Joiner GF, King FD, Middlemiss DN, Moss SF, Newman H, Riley G, Routledge C. Wyman P. 5-Chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfon-amide (SB-271046): a potent, selective, and orally bioavailable 5-HT6 receptor antagonist. J. Med. Chem. 1999; 42:202-205.
89. Trani G, Baddeley SM, Briggs MA, Chuang TT, Deeks NJ, Johnson CN, Khazragi AA, Mead TL, Medhurst AD, Milner PH, Quinn LP, Ray AM, Rivers DA, Stean TO, Stemp G, Trail BK, Witty DR. Tricyclic azepine derivatives as selective brain penetrant 5-HT6 receptor antagonists. Bioorg. Med. Chem. Lett. 2008; 18:5698-5700.
90. Cowart M, Pratt JK, Stewart AO, Bennani YL, Esbenshade TE, Hancock AA. A new class of potent non-imidazole H(3) antagonists: 2-aminoethylbenzofurans. Bioorg. Med. Chem. Lett. 2004; 14:689-693.
91. Ashwood VA, Field MJ, Horwell DC, Julien-Larose C, Lewthwaite RA, McCleary S, MC, Raphy J, Singh L. Utilization of an intramolecular hydrogen bond to increase the CNS penetration of an NK1 receptor antagonist. J. Med. Chem. 2001; 44:2276-2285.
92. Fridén M, Winiwarter S, Jerndal G, Bengtsson O, Wan H, Bredberg U, Hammarlund-udenaes M, Antonsson M. Structure-brain exposure relationships in rat and human using a novel data set of unbound drug concentrations in brain interstitial and cerebrospinal fluids. J. Med. Chem. 2009; 52:6233-6243.