Structure-brain exposure relationships

Journal of Medicinal Chemistry

Volumn 49, Issue 26, 2006, Pages 7559-7583

  Hitchcock, Stephen A ^a   Pennington, Lewis D ^a  

^a AMGEN INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 (2 METHYL 6 BENZOXAZOLYL) 3 (1,5 NAPHTHYRIDIN 4 YL)UREA; 1 DEOXYNOJIRIMYCIN; 3 (5 CHLORO 2 METHOXYPHENYL) 3 FLUORO 2,3 DIHYDRO 6 TRIFLUOROMETHYL 1H INDOL 2 ONE; 5 CHLORO N [4 METHOXY 3 (1 PIPERAZINYL)PHENYL] 3 METHYL 2 BENZOTHIOPHENESULFONAMIDE; 6 OXO 3 (2 PHENYLPYRAZOLO[1,5 A]PYRIDIN 3 YL) 1(6H) PYRIDAZINEBUTYRIC ACID; [2 [(2 HYDROXYCYCLOHEXYL)AMINO] 1 (1H INDOL 3 YLMETHYL) 1 METHYL 2 OXOETHYL]CARBAMIC ACID 2 ADAMANTYL ESTER; ABC TRANSPORTER; ALBUMIN; ARR 17779; BREAST CANCER RESISTANCE PROTEIN; CARBAMIC ACID DERIVATIVE; CARBOXYLIC ACID DERIVATIVE; CENTRAL NERVOUS SYSTEM AGENTS; DEFERIPRONE; FLUORODEOXYGLUCOSE; FLUOXETINE; FLURBIPROFEN; FR 166124; HISTAMINE H2 RECEPTOR ANTAGONIST; L 368730; LIPOPROTEIN ASSOCIATED PHOSPHOLIPASE A2; MULTIDRUG RESISTANCE PROTEIN; N [2 [4 (2 METHOXYPHENYL) 1 PIPERAZINYL]ETHYL] N (2 PYRIDYL)CYCLOHEXANECARBOXAMIDE; N [4 [2 (6 CYANO 1,2,3,4 TETRAHYDRO 2 ISOQUINOLINYL)ETHYL]CYCLOHEXYL] 4 QUINOLINECARBOXAMIDE; OREXIN A; OREXIN B; OROSOMUCOID; PHOSPHOLIPASE A2; PHOSPHOLIPASE A2 INHIBITOR; PYRIMIDINONE DERIVATIVE; QUINOXALINE DERIVATIVE; RADIOISOTOPE; RISPERIDONE; RPR 104632; SB 258510; SEROTONIN 3 AGONIST; SEROTONIN 6 ANTAGONIST; T 138067; TRACER; UNCLASSIFIED DRUG; UNINDEXED DRUG; UREA DERIVATIVE;

ACTIVE TRANSPORT; ALZHEIMER DISEASE; AREA UNDER THE CURVE; BLOOD BRAIN BARRIER; CAPILLARY PERMEABILITY; DIFFUSION; DRUG BLOOD LEVEL; DRUG BRAIN LEVEL; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG MECHANISM; DRUG PENETRATION; DRUG PROTEIN BINDING; DRUG TRANSPORT; HUMAN; HYDROGEN BOND; HYDROPHILICITY; LIPOPHILICITY; LIVER CLEARANCE; MACROMOLECULE; MEMBRANE PERMEABILITY; NEUROLOGIC DISEASE; NONHUMAN; PARKINSON DISEASE; PHYSICAL CHEMISTRY; PREDICTION; RELIABILITY; REVIEW; STRUCTURE ACTIVITY RELATION;

ANIMALS; BLOOD-BRAIN BARRIER; BRAIN; BRAIN CHEMISTRY; ENVIRONMENTAL EXPOSURE; HUMANS; NEUROTRANSMITTER AGENTS; PERMEABILITY;

EID: 33845937770     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm060642i     Document Type: Review

References (137)

1. The Blood-Brain Barrier: Biology and Research Protocols; Nag, S., Ed.; Methods in Molecular Medicine; Humana Press: Totowa, NJ, 2003; Vol. 89.
2. (a) Pardridge, W. M. Transport of Small Molecules through the Blood-Brain Barrier; Biology and Methodology. Adv. Drug Delivery Rev. 1995, 15, 5-36.
3. (b) Introduction to the Blood-Brain Barrier: Methodology, Biology and Pathology; Pardridge, W. M., Ed.; Cambridge University Press: New York, 1998.
4. (c) Pardridge, W. M. Blood-Brain Barrier Drug Targeting: The Future of Brain Drug Development. Mol. Interventions 2003, 3, 90-105.
5. (a) Aigner, A.; Wolf, S.; Gassen, G. H. Transport and Detoxification: Principles, Approaches, and Perspectives for Research on the Blood-Brain Barrier. Angew. Chem., Int. Ed. Engl. 1997, 36, 25-41.
6. (b) El-Bacha, R. S.; Minn, A. Drug Metabolizing Enzymes in Cerebrovascular Endothelial Cells Afford a Metabolic Protection to the Brain. Cell. Mol. Biol. 1999, 45, 15-23.
7. (c) Minn, A.; Ghersi-Egea, J.-F.; Perrin, R.; Leininger, B.; Siest, G. Drug Metabolizing Enzymes in the Brain and Cerebral Microvessels. Brain Res. Rev. 1991, 16, 65-82.
8. de Boer, A. G.; van der Sandt, I. C. J.; Gaillard, P. J. The Role of Drug Transporters at the Blood-Brain Barrier. Annu. Rev. Pharmacol. Toxicol. 2003, 43, 629-656.
9. Bradbury, M. W. History and Physiology of the Blood-Brain Barrier in Relation to Delivery of Drugs to the Brain. In The Blood-Brain Barrier and Drug Delivery to the CNS; Begley, D. J., Bradbury, M. W., Kreuter, J., Eds.; Marcel Dekker: New York, 2000; pp 1-7.
10. (a) Clark, D. E. Computational Prediction of Blood-Brain Barrier Permeation. Annu. Rep. Med. Chem. 2005, 40, 403-415.
11. (b) Clark, D. E. In Silico Prediction of Blood-Brain Barrier Permeation. Drug Discovery Today 2003, 8, 927-933.
12. (c) Kaznessis, Y. N. A Review of Methods for Computational Prediction of Blood-Brain Partitioning. Curr. Med. Chem.: Cent. Nerv. Syst. Agents 2005, 5, 185-191.
13. (d) Goodwin, J. T.; Clark, D. E. In Silico Predictions of Blood-Brain Barrier Penetration: Considerations To "Keep in Mind." J. Pharmacol. Exp. Ther. 2005, 315, 477-483.
14. (e) Ecker, G. F.; Noe, C. R. In Silico Prediction Models for Blood-Brain Barrier Permeation. Curr. Med. Chem. 2004, 11, 1617-1628.
15. (a) Terasaki, T.; Ohtsuki, S.; Hori, S.; Takanaga, H.; Nakashima, E.; Hosoya, K.-i. New Approaches to in Vitro Models of Blood-Brain Barrier Drug Transport. Drug Discovery Today 2003, 8, 944-954.
16. (b) Garberg, P.; Ball, M.; Borg, N.; Cecchelli, R.; Fenart, L.; Hurst, R. D.; Lindmark, T.; Mabondzo, A.; Nilsson, J. E.; Raub, T. J.; Stanimirovic, D.; Terasaki, T.; Öberg, J.-O.; Österberg, T. In Vitro Models for the Blood-Brain Barrier. Toxicol. in Vitro 2005, 19, 299-334.
17. (a) Abbott, N. J. Prediction of Blood-Brain Barrier Permeation in Drug Discovery from in Vivo, in Vitro and in Silico Models. Drug Discovery Today: Technol. 2004, 1, 407-416.
18. (b) Feng, M. R. Assessment of Blood-Brain Barrier Penetration: In Silico, in Vitro and in Vivo. Curr. Drug Metab. 2002, 3, 647-657.
19. Raub, T. J. P-Glycoprotein Recognition of Substrates and Circumvention through Rational Drug Design. Mol. Pharm. 2005, 3, 3-25.
20. (a) Bickel, U.; Yoshikawa, T.; Pardridge, W. M. Delivery of Peptides and Proteins through the Blood-Brain Barrier. Adv. Drug Delivery Rev. 2001, 46, 247-279.
21. (b) Prokai-Tatrai, K.; Prokai, L. Modifying Peptide Properties by Prodrug Design for Enhanced Transport into the CNS. In Peptide Transport and Delivery into the Central Nervous System; Prokai-Tatrai, K., Prokai, L., Eds.; Progress in Drug Research; Birkhäuser Verlag: Basel, Switzerland, 2003; pp 155-188.
22. (a) Narayanan, R.; Gunturi, S. B. In Silico ADME Modelling: Prediction Models for Blood-Brain Barrier Permeation Using a Systematic Variable Selection Method. Bioorg. Med. Chem. 2005, 13, 3017-3028.
23. (b) Ma, X.-l.; Chen, C.; Yang, J. Predictive Model of Blood-Brain Barrier Penetration of Organic Compounds. Acta Pharmacol. Sin. 2005, 26, 500-512.
24. (c) Lessigiarska, I.; Pajeva, I.; Cronin, M. T. D.; Worth, A. P. 3D QSAR Investigation of the Blood-Brain Barrier Penetration of Chemical Compounds. SAR QSAR Environ. Res. 2005, 16, 79-91.
25. (d) Winkler, D. A.; Burden, F. R. Modelling Blood-Brain Barrier Partitioning Using Bayesian Neural Nets. J. Mol. Graphics Modell. 2004, 22, 499-505.
26. (e) Liu, X.; Tu, M.; Kelly, R. S.; Chen, C.; Smith, B. J. Development of a Computational Approach To Predict Blood-Brain Barrier Permeability. Drug Metab. Dispos. 2004, 32, 132-139.
27. Faassen, F.; Vogel, G.; Spanings, H.; Vromans, H. Caco-2 Permeability, P-Glycoprotein Transport Ratios and Brain Penetration of Heterocyclic Drugs. Int. J. Pharm. 2003, 263, 113-122.
28. Avdeef, A. The Rise of PAMPA. Expert Opin. Drug Metab. Toxicol. 2005, 1, 325-342.
29. (a) Reichel, A.; Begley, D. J. Potential of Immobilized Artificial Membranes for Predicting Drug Penetration across the Blood-Brain Barrier. Pharm. Res. 1998, 15, 1270-1274.
30. (b) Yoon, C. H.; Kim, S. J.; Shin, B. S.; Lee, K. C.; Yoo, S. D. Rapid Screening of Blood-Brain Barrier Penetration of Drugs Using the Immobilized Artificial Membrane Phosphatidylcholine Column Chromatography. J. Biomol. Screening 2006, 11, 13-20.
31. (a) Hansen, D. K.; Scott, D. O.; Otis, K. W.; Lunte, S. M. Comparison of in Vitro BBMEC Permeability and in Vivo CNS Uptake by Microdialysis Sampling. J. Pharm. Biomed. Anal. 2002, 27, 945-958.
32. (b) Lundquist, S.; Renftel, M.; Brillault, J.; Fenart, L.; Cecchelli, R.; Dehouck, M.-P. Prediction of Drug Transport through the Blood-Brain Barrier in Vivo: A Comparison between Two in Vitro Models. Pharm. Res. 2002, 19, 976-981.
33. Wang, Q.; Rager, J. D.; Weinstein, K.; Kardos, P. S.; Dobson, G. L.; Li, J.; Hidalgo, I. J. Evaluation of the MDR-MDCK Cell Line as a Permeability Screen for the Blood-Brain Barrier. Int. J. Pharm. 2005, 288, 349-359.
34. Maurer, T. S.; DeBartolo, D. B.; Tess, D. A.; Scott, D. O. Relationship between Exposure and Nonspecific Binding of Thirty-Three Central Nervous System Drugs in Mice. Drug Metab. Dispos. 2005, 33, 175-181.
35. (a) Liu, X.; Smith, B. J.; Chen, C.; Callegari, E.; Becker, S. L.; Chen, X.; Cianfrogna, J.; Doran, A. C.; Doran, S. D.; Gibbs, J. P.; Hosea, N.; Liu, J.; Nelson, F. R.; Szewc, M. A.; Van Deusen, J. Use of a Physiologically Based Pharmocokinetic 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. Ther. 2005, 313, 1254-1262.
36. (b) Liu, X.; Chen, C. Strategies To Optimize Brain Penetration in Drug Discovery. Curr. Opin. Drug Discovery Dev. 2005, 8, 505-512.
37. Summerfield, S. G.; Stevens, A. J.; Cutler, L.; del Carmen, Osuna, M.; Hammond, B.; Tang, S.-P.; Hersey, A.; Spalding, D. J.; Jeffrey, P. Improving the in Vitro Prediction of in Vivo Central Nervous System Penetration: Integrating Permeability, P-glycoprotein Efflux, and Free Fractions in Blood and Brain. J. Pharmacol. Exp. Ther. 2006, 316, 1282-1290.
38. (a) Laruelle, M.; Slifstein, M.; Huang, Y. Relationships between Radiotracer Properties and Image Quality in Molecular Imaging of the Brain with Positron Emission Tomography. Mol. Imaging Biol. 2003, 5, 363-375.
39. (b) Waterhouse, R. N. Determination of Lipophilicity and Its Use as a Predictor of Blood-Brain Barrier Penetration of Molecular Imaging Agents. Mol. Imaging Biol. 2003, 5, 376-389.
40. Takasato, Y.; Rapoport, S. I.; Smith, Q. R. An in Situ Brain Perfusion Technique To Study Cerebrovascular Transport in the Rat. Am. J. Physiol. 1984, 247, H484-H493.
41. Chernet, E.; Martin, L. J.; Li, D.; Need, A. B.; Barth, V. N.; Rash, K. S.; Phebus, L. A. Use of LC/MS To Assess Brain Tracer Distribution in Preclinical, in Vivo Receptor Occupancy Studies: Dopamine D2, Serotonin 2A and NK-1 Receptors as Examples. Life Sci. 2005, 78, 340-346.
42. Overton, E. Vierteljahrsschr. Naturforsch. Ges. Zuerich 1899, 44, 88-135.
43. Soloway, A. H. Correlation of Drug Penetration of Brain and Chemical Structure. Science 1958, 128, 1572-1574.
44. (a) Hansch, C.; Björkroth, J. P.; Leo, A. Hydrophobicity and Central Nervous System Agents: On the Principle of Minimal Hydrophobicity in Drug Design. J. Pharm. Sci. 1987, 76, 663-687.
45. (b) Glave, W. R.; Hansch, C. Relationship between Lipophilic Character and Anesthetic Activity. J. Pharm. Sci. 1972, 61, 589-591.
46. Young, R. C.; Mitchell, R. C.; Brown, T. H.; Ganellin, C. R.; Griffiths, R.; Jones, M.; Rana, K. K.; Saunders, D.; Smith, I. R.; Sore, N. E.; Wilks, T. J. Development of a New Physicochemical Model for Brain Penetration and Its Application to the Design of Centrally Acting H2 Receptor Histamine Antagonists. J. Med. Chem. 1988, 31, 656-671.
47. (a) Lipinski, C. A. Lead- and Drug-like Compounds: The Rule-of-Five Revolution. Drug Discovery Today: Technol. 2004, 1, 337-341.
48. (b) Lipinski, C.; Hopkins, A. Navigating Chemical Space for Biology and Medicine. Nature 2004, 432, 855-861.
49. (c) Lipinski, C. A. Drug-like Properties and the Causes of Poor Solubility and Poor Permeability. J. Pharmacol. Toxicol. Methods 2000, 44, 235-249.
50. Mahar Doan, K. M.; Humphreys, J. E.; Webster, L. O.; Wring, S. A.; Shampine, L. J.; Serabjit-Singh, C. J.; Adkison, K. K.; Polli, J. W. Passive Permeability and P-Glycoprotein-Mediated Efflux Differentiate Central Nervous System (CNS) and Non-CNS Marketed Drugs. J. Pharmacol. Exp. Ther. 2002, 303, 1029-1037.
51. (a) Begley, D. J. ABC Transporters and the Blood-Brain Barrier. Curr. Pharm. Des. 2004, 10, 1295-1312.
52. (b) Fromm, M. F. Importance of P-Glycoprotein at Blood-Tissue Barriers. Trends Pharmacol. Sci. 2004, 23, 423-429.
53. (c) Laplante, A.; Jodoin, J.; Demeule, M.; Béliveau, R. P-Glycoprotein: A Key Player in the Blood-Brain Barrier. Recent Res. Dev. Biochem. 2000, 2, 51-64.
54. Kusuhara, H.; Sugiyama, Y. Active Efflux across the Blood-Brain Barrier: Role of the Solute Carrier Family. NeuroRx 2005, 2, 73-85.
55. Schinkel, A. H.; Smit, J. J. M.; van Tellingen, O.; Beijnen, J. H.; Wagenaar, E.; van Deemter, L.; Mol, C. A. A. M.; van der Valk, M. A.; Robanus-Maandag, E. C.; te Riele, H. P. J.; Berns, A. J. M.; Borst, P. Disruption of the Mouse mdr1a P-Glycoprotein Gene Leads to a Deficiency in the Blood-Brain Barrier and to Increased Sensitivity to Drugs. Cell 1994, 77, 491-502.
56. Doran, A.; Obach, R. S.; Smith, B. J.; Hosea, N. A.; Becker, S.; Callegari, E.; Chen, C.; Chen, X.; Choo, E.; Cianfrogna, J.; Cox, L. M.; Gibbs, J. P.; Gibbs, M. A.; Hatch, H.; Hop, C. E. C. A.; Kasman, I. N.; LaPerle, J.; Liu, J.; Liu, X.; Logman, M.; Maclin, D.; Nedza, F. M.; Nelson, F.; Olson, E.; Rahematpura, S.; Raunig, D.; Rogers, S.; Schmidt, K.; Spracklin, D. K.; Szewc, M.; Troutman, M.; Tseng, E.; Tu, M.; Van, Deusen, J. W.; Venkatakrishnan, K.; Walens, G.; Wang, E. Q.; Wong, D.; Yasgar, A. S.; 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.
57. Seelig, A. How Does P-Glycoprotein Recognize Its Substrates? Int. J. Clin. Pharmacol. Ther. 1998, 36, 50-54.
58. Abraham, M. H. The Factors That Influence Permeation across the Blood-Brain Barrier. Eur. J. Med. Chem. 2004, 39, 235-240.
59. Gratton, J. A.; Abraham, M. H.; Bradbury, M. W.; Chadha, H. S. Molecular Factors Influencing Drug Transfer across the Blood-Brain Barrier. J. Pharm. Pharmacol. 1997, 49, 1211-1216.
60. (a) Atkinson, F.; Cole, S.; Green, C.; van de Waterbeemd, H. Lipophilicity and Other Parameters Affecting Brain Penetration. Curr. Med. Chem.: Cent. Nerv. Syst. Agents 2002, 2, 229-240.
61. (b) van de Waterbeemd, H.; Camenisch, G.; Folkers, G.; Chretien, J. R.; Raevsky, O. A. Estimation of Blood-Brain Barrier Crossing of Drugs Using Molecular Size and Shape, and H-Bonding Descriptors. J. Drug Targeting 1998, 6, 151-165.
62. (a) Unless otherwise specified, all physicochemical properties in the figure tables were calculated using Advanced Chemistry Development (ACD/Labs) software (Web site: www.acdlabs.com) except for clogP values, which were obtained using Daylight Chemical Information Systems software (Web site: www.daylight.com).
63. (b) Abbreviations employed in the figure tables: molecular weight (MW), polar surface area (PSA) in Å2, calculated log P (cLogP), calculated log D (cLogD), and hydrogen bond donors (HBD).
64. Ahmed, M.; Briggs, M. A.; Bromidge, S. M.; Buck, T.; Campbell, L.; Deeks, N. J.; Garner, A.; Gordon, L.; Hamprecht, D. W.; Holland, V.; Johnson, C. N.; Medhurst, A. D.; Mitchell, D. J.; Moss, S. F.; Powles, J.; Seal, J. T.; Stean, T. O.; Stemp, G.; Thompson, M.; Trail, B.; Upton, N.; Winborn, K.; Witty, D. R. Bicyclic Heteroarylpiperazines as Selective Brain Penetrant 5-HT6 Receptor Antagonists. Bioorg. Med. Chem. Lett. 2005, 15, 4867-4871.
65. (a) Tatsumi, R.; Fujio, M.; Satoh, H.; Katayama, J.; Takanashi, S.-i.; Hashimoto, K.; Tanaka, H. Discovery of the a7 Nicotinic Acetylcholine Receptor Agonists. (R)-3′-(5-Chlorothiophen-2-yl)-spiro-1-azabicyclo[2.2.2]octane- 3,5′-[1′,3′]oxazolidin-2′-one as a Novel, Potent, Selective, and Orally Bioavailable Ligand. J. Med. Chem. 2005, 48, 2678-2686.
66. (b) Tatsumi, R.; Seio, K.; Fujio, M.; Katayama, J.; Horikawa, T.; Hashimoto, K.; Tanaka, H. (+)-3-[2-(Benzo[b]-thiophen-2-yl)-2-oxoethyl]-1- azabicyclo[2.2.2]octane as Potent Agonists for the α7 Nicotinic Acetylcholine Receptor. Bioorg. Med. Chem. Lett. 2004, 14, 3781-3784.
67. Campiani, G.; Morelli, E.; Gemma, S.; Nacci, V.; Butini, S.; Hamon, M.; Novellino, E.; Greco, G.; Cagnotto, A.; Goegan, M.; Cervo, L.; Valle, F. D.; Fracasso, C.; Caccia, S.; Mennini, T. Pyrroloquinoxaline Derivatives as High-Affinity and Selective 5-HT3 Receptor Agonists: Synthesis, Further Structure-Activity Relationships, and Biological Studies. J. Med. Chem. 1999, 42, 4362-4379.
68. Campiani, G.; Cappelli, A.; Nacci, V.; Anzini, M.; Vomero, S.; Hamon, M.; Cagnotto, A.; Fracasso, C.; Uboldi, C.; Caccia, S.; Consolo, S.; Mennini, T. Novel and Highly Potent 5-HT3 Receptor Agonists Based on a Pyrroloquinoxaline Structure. J. Med. Chem. 1997, 40, 3670-3678.
69. Habgood, M. D.; Liu, Z. D.; Dehkordi, L. S.; Khodr, H. H.; Abbott, J.; Hider, R. C. Investigation into the Correlation between the Structure of Hydroxypyridinones and Blood-Brain Barrier Permeability. Biochem. Pharmacol. 1999, 57, 1305-1310.
70. Boyd, H. F.; Hammond, B.; Hickey, D. M. B.; Ife, R. J.; Leach, C. A.; Lewis, V. A.; Macphee, C. H.; Milliner, K. J.; Pinto, I. L.; Smith, S. A.; Stansfield, I. G.; Theobald, C. J.; Whittaker, C. M. The Identification of a Potent, Water Soluble Inhibitor of Lipoprotein-Associated Phospholipase A2. Bioorg. Med. Chem. Lett. 2001, 11, 701-704.
71. Boyd, H. F.; Fell, S. C. M.; Flynn, S. T.; Hickey, D. M. B.; Ife, R. J.; Leach, C. A.; Macphee, C. H.; Milliner, K. J.; Moores, K. E.; Pinto, I. L.; Porter, R. A.; Rawlings, A. D.; Smith, S. A.; Stansfield, I. G.; Tew, D. G.; Theobald, C. J.; Whittaker, C. M. N-1 Substituted Pyrimidin-4-ones: Novel, Orally Active Inhibitors of Lipoprotein-Associated Phospholipase A2. Bioorg. Med. Chem. Lett. 2000, 10, 2557-2561.
72. Xu, Y.; Choi, S.-R.; Kung, M.-P.; Kung, H. F. Synthesis of Radioiodinated 1-Deoxy-Nojirimycin Derivatives: Novel Glucose Analogs. Nucl. Med. Biol. 1999, 26, 833-839.
73. Zhuang, Z.-P.; Kung, M.-P.; Hou, C.; Skovronsky, D. M.; Gur, T. L.; Plössl, K.; Trojanowski, J. Q.; Lee, V. M.-Y.; Kung, H. F. Radioiodinated Styrylbenzenes and Thioflavins as Probes for Amyloid Aggregates. J. Med. Chem. 2001, 44, 1905-1914.
74. Sakurai, T.; Amemiya, A.; Ishii, M.; Matsuzaki, I.; Chemelli, R. M.; Tanaka, H.; Williams, S. C.; Richardson, J. A.; Kozlowski, G. P.; Wilson, S.; Arch, J. R. S.; Buckingham, R. E.; Haynes, A. C.; Carr, S. A.; Annan, R. S.; McNulty, D. E.; Liu, W.-S.; Terrett, J. A.; Elshourbagy, N. A.; Bergsma, D. J.; Yanagisawa, M. Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors That Regulate Feeding Behavior. Cell 1998, 92, 573-585.
75. Porter, R. A.; Chan, W. N.; Coulton, S.; Johns, A.; Hadley, M. S.; Widdowson, K.; Jerman, J. J. C.; Brough, S. J.; Coldwell, M.; Smart, D.; Jewitt, F.; Jeffrey, P.; Austin, N. 1,3-Biarylureas as Selective Non-Peptide Antagonists of the Orexin-1 Receptor. Bioorg. Med. Chem. Lett 2001, 11, 1907-1910.
76. Stemp, G.; Ashmeade, T.; Branch, C. L.; Hadley, M. S.; Hunter, A. J.; Johnson, C. N.; Nash, D. J.; Thewlis, K. M.; Vong, A. K. K.; Austin, N. E.; Jeffrey, P.; Avenell, K. Y.; Boyfield, I.; Hagan, J. J.; Middlemiss, D. N.; Reavill, C.; Riley, G. J.; Routledge, C.; Wood, M. Design and Synthesis of trans-N-[4-[2-(6-Cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl] cyclohexyl]-4-quinolinecarboxamide (SB-277011): A Potent and Selective Dopamine D3 Receptor Antagonist with High Oral Bioavailability and CNS Penetration in the Rat. J. Med. Chem. 2000, 43, 1878-1885.
77. Vasudevan, A.; Souers, A. J.; Freeman, J. C.; Verzal, M. D.; Gao, J.; Mulhern, M. M.; Wodka, D.; Lynch, J. K.; Engstrom, K. M.; Wagaw, S. H.; Brodjian, S.; Dayton, B.; Falls, D. H.; Bush, E.; Brune, M.; Shapiro, R. D.; Marsh, K. C.; Hernandez, L. E.; Collins, C. A.; Kym, P. R. Aminopiperidine Indazoles as Orally Efficacious Melanin Concentrating Hormone Receptor-1 Antagonists. Bioorg. Med. Chem. Lett. 2005, 15, 5293-5297.
78. (a) Bromidge, S. M.; Clarke, S. E.; King, F. D.; Lovell, P. J.; Newman, H.; Riley, G.; Routledge, C.; Serafinowska, H. T.; Smith, D. R.; Thomas, D. R. Bicyclic Piperazinylbenzenesulphonamides Are Potent and Selective 5-HT6 Receptor Antagonists. Bioorg. Med. Chem. Lett. 2002, 12, 1357-1360.
79. (b) Bromidge, S. M.; Brown, A. M.; Clarke, S. E.; Dodgson, K.; Gager, T.; Grassam, H. L.; Jeffrey, P. M.; Joiner, G. F.; King, F. D.; Middlemiss, D. N.; Moss, S. F.; Newman, H.; Riley, G.; Routledge, C.; Wyman, P. 5-Chloro-N-(4-methoxy-3-piperazin-1-ylphenyl)-3-methyl-2- benzothiophenesulfonamide (SB-271046): A Potent, Selective, and Orally Bioavailable 5-HT6 Receptor Antagonist. J. Med. Chem. 1999, 42, 202-205.
80. Fura, A.; Shu, Y.-Z.; Zhu, M.; Hanson, R. L.; Roongta, V.; Humphreys, W. G. Discovering Drugs through Biological Transformation: Role of Pharmacologically Active Metabolites in Drug Discovery. J. Med. Chem. 2004, 47, 4339-4351.
81. Hughes, J.; Boden, P.; Costall, B.; Domeney, A.; Kelly, E.; Horwell, D. C.; Hunter, J. C.; Pinnock, R. D.; Woodruff, G. N. Development of a Class of Selective Cholecystokinin Type B Receptor Antagonists Having Potent Anxiolytic Activity. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 6728-6732.
82. Trivedi, B. K.; Padia, J. K.; Holmes, A.; Rose, S.; Wright, D. S.; Hinton, J. P.; Pritchard, M. C.; Eden, J. M.; Kneen, C.; Webdale, L.; Suman-Chauhan, N.; Boden, P.; Singh, L.; Field, M. J.; Hill, D. Second Generation "Peptoid" CCK-B Receptor Antagonists: Identification and Development of N-(Adamantyloxycarbonyl)-α-methyl-(R)- tryptophan Derivative (CI-1015) with an Improved Pharmacokinetic Profile. J. Med. Chem. 1998, 41, 38-45.
83. Castro, J. L.; Ball, R. G.; Broughton, H. B.; Russell, M. G. N.; Rathbone, D.; Watt, A. P.; Baker, R.; Chapman, K. L.; Fletcher, A. E.; Patel, S.; Smith, A. J.; Marshall, G. R.; Ryecroft, W.; Matassa, V. G. Controlled Modification of Acidity in Cholecystokinin B Receptor Antagonists: N-(1,4-Benzodiazepin-3-yl)-N′-[3-(tetrazol-5-ylamino)phenyl] ureas. J. Med. Chem. 1996, 39, 842-849.
84. Pinkerton, A. B.; Cube, R. V.; Hutchinson, J. H.; James, J. K.; Gardner, M. F.; Schaffhauser, H.; Rowe, B. A.; Daggett, L. P.; Vernier, J.-M. Allosteric Potentiators of the Metabotropic Glutamate Receptor 2 (mGlu2). Part 2: 4-Thiopyridyl Acetophenones as Non-Tetrazole Containing mGlu2 Receptor Potentiators. Bioorg. Med. Chem. Lett. 2004, 14, 5867-5872.
85. Bonnefous, C.; Vernier, J.-M.; Hutchinson, J. H.; Gardner, M. F.; Cramer, M.; James, J. K.; Rowe, B. A.; Daggett, L. P.; Schaffhauser, H.; Kamenecka, T. M. Biphenyl-Indanones: Allosteric Potentiators of the Metabotropic Glutamate Subtype 2 Receptor. Bioorg. Med. Chem. Lett. 2005, 15, 4354-4358.
86. Govek, S. P.; Bonnefous, C.; Hutchinson, J. H.; Kamenecka, T.; McQuiston, J.; Pracitto, R.; Zhao, L. X.; Gardner, M. F.; James, J. K.; Daggett, L. P.; Rowe, B. A.; Schaffhauser, H.; Bristow, L. J.; Campbell, U. C.; Rodriguez, D. E.; Vernier, J.-M. Benzazoles as Allosteric Potentiators of Metabotropic Glutamate Receptor 2 (mGluR2): Efficacy in an Animal Model for Schizophrenia. Bioorg. Med. Chem. Lett. 2005, 15, 4068-4072.
87. Cube, R. V.; Vernier, J.-M.; Hutchinson, J. H.; Gardner, M. F.; James, J. K.; Rowe, B. A.; Schaffhauser, H.; Daggett, L.; Pinkerton, A. B. 3-(2-Ethoxy-4-{4-[3-hydroxy-2-methyl-4-(3-methylbutanoyl)phenoxy]butoxy}phenyl) propanoic Acid: A Brain Penetrant Allosteric Potentiator at the Metabotropic Glutamate Receptor 2 (mGluR2). Bioorg. Med. Chem. Lett. 2005, 15, 2389-2393.
88. 42 in Vivo. J. Clin. Invest. 2003, 112, 440-449.
89. (b) Yan, Q.; Zhang, J.; Liu, H.; Babu-Khan, S.; Vassar, R.; Biere, A. L.; Citron, M.; Landreth, G. Anti-Inflammatory Drug Therapy Alters β-Amyloid Processing and Deposition in an Animal Model of Alzheimer's Disease. J. Neurosci. 2003, 23, 7504-7509.
90. 42 and Change Presenilin 1 Conformation. Nat. Med. 2004, 10, 1065-1066.
91. 1-42 Secretion. J. Med. Chem. 2005, 48, 5705-5720.
92. Kuroda, S.; Takamura, F.; Tenda, Y.; Itani, H.; Tomishima, Y.; Akahane, A.; Sakane, K. Design, Synthesis and Biological Evaluation of a Novel Series of Potent, Orally Active Adenosine A1 Receptor Antagonists with High Blood-Brain Barrier Permeability. Chem. Pharm. Bull. 2001, 49, 988-998.
93. (a) Hewawasam, P.; Gribkoff, V. K.; Pendri, Y.; Dworetzky, S. I.; Meanwell, N. A.; Martinez, E.; Boissard, C. G.; Post-Munson, D. J.; Trojnacki, J. T.; Yeleswaram, K.; Pajor, L. M.; Knipe, J.; Gao, Q.; Perrone, R.; Starrett, J. E. The Synthesis and Characterization of BMS-204352 (MaxiPost) and Related 3-Fluorooxindoles as Openers of Maxi-K Potassium Channels. Bioorg. Med. Chem. Lett. 2002, 12, 1023-1026.
94. (b) Hewawasam, P.; Fan, W.; Knipe, J.; Moon, S. L.; Boissard, C. G.; Gribkoff, V. K.; Starrett, J. E. The Synthesis and Structure-Activity Relationships of 4-Aryl-3-aminoquinolin-2-ones: A New Class of Calcium-Dependent, Large Conductance, Potassium (Maxi-K) Channel Openers Targeted for Post-Stroke Neuroprotection. Bioorg. Med. Chem. Lett. 2002, 12, 1779-1783.
95. Anderson, B. D. Prodrugs for Improved CNS Delivery. Adv. Drug Delivery Rev. 1996, 19, 171-202.
96. Deguchi, Y.; Hayashi, H.; Fujii, S.; Naito, T.; Yokoyama, Y.; Yamada, S.; Kimura, R. Improved Brain Delivery of a Nonsteroidal Anti-Inflammatory Drug with a Synthetic Glyceride Ester: A Preliminary Attempt at a CNS Drug Delivery System for the Therapy of Alzheimer's Disease. J. Drug Targeting 2000, 8, 371-381.
97. Kotra, L. P.; Manouilov, K. K.; Cretton-Scott, E.; Sommadossi, J.-P.; Boudinot, F. D.; Schinazi, R. F.; Chu, C. K. Synthesis, Biotransformation, and Pharmacokinetic Studies of 9-(β-D-Arabinofuranosyl)-6-azidopurine: A Prodrug for Ara-A Designed To Utilize the Azide Reduction Pathway. J. Med. Chem. 1996, 39, 5202-5207.
98. 6-Methyl- 2′,3′-dideoxy-2′-fluoro-β-D-arabinofuranosyladenine as Prodrugs of the Anti-HIV Nucleosides 2′-F-ara-ddA and 2′-F-ara-ddI. J. Med. Chem. 1996, 39, 4676-4681.
99. (b) Shanmuganathan, K.; Koudriakova, T.; Nampalli, S.; Du, J.; Gallo, J. M.; Schinazi, R. F.; Chu, C. K. Enhanced Brain Delivery of an Anti-HIV Nucleoside 2′-F-ara-ddI by Xanthine Oxidase Mediated Biotransformation. J. Med. Chem. 1994, 37, 821-827.
100. Prokai, L.; Prokai-Tatrai, K.; Bodor, N. Targeting Drugs to the Brain by Redox Chemical Delivery Systems. Med. Res. Rev. 2000, 20, 367-416.
101. Yiu, S.-h.; Knaus, E. E. Synthesis, Biological Evaluation, Calcium Channel Antagonist Activity, and Anticonvulsant Activity of Felodipine Coupled to a Dihydropyridine-Pyridinium Salt Redox Chemical Delivery System. J. Med. Chem. 1996, 39, 4576-4582.
102. Kimberly, W. T.; Esler, W. P.; Ye, W.; Ostaszewski, B. L.; Gao, J.; Diehl, T.; Selkoe, D. J.; Wolfe, M. S. Notch and the Amyloid Precursor Protein Are Cleaved by Similar γ-Secretase(s). Biochemistry 2003, 42, 137-144.
103. Laras, Y.; Quéléver, G.; Garino, C.; Pietrancosta, N.; Sheha, M.; Bihel, F.; Wolfe, M. S.; Kraus, J.-L. Substituted Thiazolamide Coupled to a Redox Delivery System: A New γ-Secretase Inhibitor with Enhanced Pharmacokinetic Profile. Org. Biomol. Chem. 2005, 3, 612-618.
104. Yordanov, A. T.; Yamada, K.-i.; Krishna, M. C.; Russo, A.; Yoo, J.; English, S.; Mitchell, J. B.; Brechbiel, M. W. Acyl-Protected Hydroxylamines as Spin Label Generators for EPR Brain Imaging. J. Med. Chem. 2002, 45, 2283-2288.
105. (a) Yokoyama, H.; Itoh, O.; Aoyama, M.; Obara, H.; Ohya, H.; Kamada, H. In Vivo EPR Imaging by Using an Acyl-Protected Hydroxylamine To Analyze Intracerebral Oxidative Stress in Rats after Epileptic Seizures. Magn. Reson. Imaging 2000, 18, 875-879.
106. (b) Yokoyama, H.; Itoh, O.; Ogata, T.; Obara, H.; Ohya-Nishiguchi, H.; Kamada, H. Temporal Brain Imaging by a Rapid Scan ESR-CT System in Rats Receiving Intraperitoneal Injection of a Methyl Ester Nitroxide Radical. Magn. Reson. Imaging 1997, 15, 1079-1984.
107. (c) Yokoyama, H.; Ogata, T.; Tsuchihashi, N.; Hiramatsu, M.; Mori, N. A Spatiotemporal Study on the Distribution of Intraperitoneally Injected Nitroxide Radical in the Rat Head Using an in Vivo ESR Imaging System. Magn. Reson. Imaging 1996, 14, 559-563.
108. Chen, C.; Hanson, H.; Watson, J. W; Lee, J. S. P-Glycoprotein Limits the Brain Penetration of Nonsedating but not Sedating Hi-Antagonists. Drug Metab. Dispos. 2003, 31, 312-318.
109. 2A Serotonin Receptor Agonist 1-(4-Bromo-2,5-dimethoxyphenyl)-2-aminopropane. J. Med. Chem. 2004, 47, 6034-6041.
110. Munk, S. A.; Harcourt, D.; Ambrus, G.; Denys, L.; Gluchowski, C.; Burke, J. A.; Kharlamb, A. B.; Manlapaz, C. A.; Padillo, E. U.; Runde, E.; Williams, L.; Wheeler, L. A.; Garst, M. E. Synthesis and Evaluation of 2-[(5-Methylbenz-1-ox-4-azin-6-yl)imino]imidazoline, a Potent, Peripherally Acting α2 Adrenoceptor Agonist. J. Med. Chem. 1996, 39, 3533-3538.
111. 1A Receptors in Vitro and in Vivo. Eur. J. Nucl. Med. 1998, 25, 338-346.
112. 1A Receptor Antagonists. Bioorg. Med. Chem. 2005, 13, 883-893.
113. Bender, D.; Holschbach, M.; Stöcklin, G. Synthesis of n.c.a Carbon-11 Labelled Clozapine and Its Major Metabolite Clozapine-N-Oxide and Comparison of Their Biodistribution in Mice. Nucl. Med. Biol. 1994, 21, 921-925.
114. Baldessarini, R. J.; Centorrino, F.; Flood, J. G.; Volpicelli, S. A.; Huston-Lyons, D.; Cohen, B. M. Tissue Concentrations of Clozapine and Its Metabolites in the Rat. Neuropsychopharmacology 1993, 9, 117-124.
115. Sveigaard, H. H.; Dalgaard, L. Evaluation of Blood-Brain Barrier Passage of a Muscarine M1 Agonist and a Series of Analogous Tetrahydropyridines Measured by in Vivo Microdialysis. Pharm. Res. 2000, 17, 70-76.
116. Rubenstein, S. M.; Baichwal, V.; Beckmann, H.; Clark, D. L.; Frankmoelle, W.; Roche, D.; Santha, E.; Schwender, S.; Thoolen, M.; Ye, Q.; Jaen, J. C. Hydrophilic. Pro-Drug Analogues of Tl38067 Are Efficacious in Controlling Tumor Growth in Vivo and Show a Decreased Ability To Cross the Blood Brain Barrier. J. Med. Chem. 2001, 44, 3599-3605.
117. (a) Tsuji, A. Small Molecular Drug Transfer Across the Blood-Brain Barrier via Carrier-Mediated Transport Systems. NeuroRx 2005, 2, 54-62.
118. (b) Sai, Y.; Tsuji, A. Transporter-Mediated Drug Delivery: Recent Progress and Experimental Approaches. Drug Discovery Today 2004, 9, 712-720.
119. (c) Tamai, I.; Tsuji, A. Transporter-Mediated Permeation of Drugs across the Blood-Brain Barrier. J. Pharm. Sci. 2000, 89, 1371-1388.
120. (d) Tsuji, A.; Tamai, I. Carrier-Mediated or Specialized Transport of Drugs across the Blood-Brain Barrier. Adv. Drug Delivery Rev. 1999, 36, 277-290.
121. Su, T.-Z.; Lunney, E.; Campbell, G.; Oxender, D. L. Transport of Gabapentin, a γ-Amino Acid Drug, by System L α-Amino Acid Transporters: A Comparative Study in Astrocytes, Synaptosomes, and CHO Cells. J. Neurochem. 1995, 64, 2125-2131.
122. Schwarz, J. B.; Gibbons, S. E.; Graham, S. R.; Colbry, N. L.; Guzzo, P. R.; Le, V.-D.; Vartanian, M. G.; Kinsora, J. J.; Lotarski, S. M.; Li, Z.; Dickerson, M. R.; Su, T.-Z.; Weber, M. L.; El-Kattan, A.; Thorpe, A. J.; Donevan, S. D.; Taylor, C. P.; Wustrow, D. J. Novel Cyclopropyl β-Amino Acid Analogues of Pregabalin and Gabapentin That Target the γ2-d Protein. J. Med. Chem. 2005, 48, 3026-3035.
123. Crooks, P. A.; Ayers, J. T.; Xu, R.; Sumithran, S. P.; Grinevich, V. P.; Wilkins, L. H.; Deaciuc, A. G.; Allen, D. D.; Dwoskin, L. P. Development of Subtype-Selective Ligands as Antagonists at Nicotinic Receptors Mediating Nicotine-Evoked Dopamine Release. Bioorg. Med. Chem. Lett. 2004, 14, 1869-1874.
124. Allen, D. D.; Lockman, P. R.; Roder, K. E.; Dwoskin, L. P.; Crooks, P. A. Active Transport of High-Affinity Choline and Nicotine Analogs into the Central Nervous System by the Blood-Brain Barrier Choline Transporter. J. Pharmacol. Exp. Ther. 2003, 304, 1268-1274.
125. Manfredini, S.; Pavan, B.; Vertuani, S.; Scaglianti, M.; Compagnone, D.; Biondi, C.; Scatturin, A.; Tanganelli, S.; Ferraro, L.; Prasad, P.; Dalpiaz, A. Design, Synthesis and Activity of Ascorbic Acid Prodrugs of Nipecotic, Kynurenic and Diclophenamic Acids, Liable To Increase Neurotropic Activity. J. Med. Chem. 2002, 45, 559-562.
126. Manfredini, S.; Vertuani, S.; Pavan, B.; Vitali, F.; Scaglianti, M.; Bortolotti, F.; Biondi, C.; Scatturin, A.; Prasad, P.; Dalpiaz, A. Design, Synthesis and in Vitro Evaluation on HRPE Cells of Ascorbic and 6-Bromoascorbic Acid Conjugates with Neuroactive Molecules. Bioorg. Med. Chem. 2004, 12, 5453-5463.
127. (a) Löscher, W.; Potschka, H. Blood-Brain Barrier Active Efflux Transporters: ATP-Binding Cassette Gene Family. NeuroRx 2005, 2, 86-98.
128. (b) Löscher, W.; Potschka, H. Role of Drug Efflux Transporters in the Brain for Drug Disposition and Treatment of Brain Diseases. Prog. Neurobiol. 2005, 76, 22-76.
129. (c) El Ela, A. A.; Härtter, S.; Schmitt, U.; Hiemke, C.; Spahn-Langguth, H.; Langguth, P. Identification of P-Glycoprotein Substrates and Inhibitors among Psychoactive Compounds. Implications for Pharmacokinetics of Selected Substrates. Pharm. Pharmacol. 2004, 56, 967-975.
130. (d) Golden, P. L.; Pollack, G. M. Blood-Brain Barrier Efflux Transport. J. Pharm. Sci. 2003, 92, 1739-1753.
131. (e) Seelig, A.; Landwojtowicz, E. Structure-Activity Relationship of P-Glycoprotein Substrates and Modifiers. Eur. J. Pharm. Sci. 2000, 12, 31-40.
132. Murata, M.; Tamai, I.; Kato, H.; Nagata, O.; Kato, H.; Tsuji, A. Efflux Transport of a New Quinolone Antibacterial Agent, HSR-903, across the Blood-Brain Barrier. J. Pharmacol. Exp. Ther. 1999, 290, 51-57.
133. Rice, A.; Liu, Y.; Michaelis, M. L.: Himes, R. H.; Georg, G. I.; Audus, K. L. Chemical Modification of Paclitaxel (Taxol) Reduces P-Glycoprotein Interactions and Increases Permeation across the Blood-Brain Barrier in Vitro and in Situ. J. Med. Chem. 2005, 48, 832-838.
134. Ojima, I.; Duclos, O.; Dormán, G.; Simonot, B.; Prestwich, G. D.; Rao, S.; Lerro, K. A.; Horwitz, S. B. A New Paclitaxel Photoaffinity Analog with a 3-(4-benzoylphenyl)propanoyl Probe for Characterization of Drug-Binding Sites on Tubulin and P-Glycoprotein. J. Med. Chem. 1995, 38, 3891-3894.
135. Liu, Y.; Ali, S. M.; Boge, T. C.; Georg, G. I.; Victory, S.; Zygmunt, J.; Marquez, R. T.; Himes, R. H. A Systematic SAR Study of C10 Modified Paclitaxel Analogues Using a Combinatorial Approach. Comb. Chem. High Throughput Screening 2002, 5, 39-48.
136. Jimonet, P.; Ribeill, Y.; Bohme, G. A.; Boireau, A.; Chevé, M.; Damour, D.; Doble, A.; Genevois-Borella, A.; Herman, F.; Imperato, A.; Le Guern, S.; Manfré, F.; Pratt, J.; Randle, J. C. R.; Stutzmann, J.-M.; Mignani, S. Indeno[1,2-b]pyrazin-2,3-diones: A New Class of Antagonists at the Glycine Site of the NMDA Receptor with Potent in Vivo Activity. J. Med. Chem. 2000, 43, 2371-2381.
137. Kuyper, L. F.; Baccanari, D. P.; Jones, M. L.; Hunter, R. N.; Tansik, R. L.; Joyner, S. S.; Boytos, C. M.; Rudolph, S. K.; Knick, V.; Wilson, H. R.; Caddell, J. M.; Friedman, H. S.; Comley, J. C. W.; Stables, J. N. High-Affinity Inhibitors of Dihydrofolate Reductase: Antimicrobial and Anticancer Activities of 7,8-Dialkyl-1,3-diaminopyrrolo[3,2-f]quinazolines with Small Molecular Size. J. Med. Chem. 1996, 39, 892-903.