CNS Drug Design: Balancing Physicochemical Properties for Optimal Brain Exposure

Journal of Medicinal Chemistry

Volumn 58, Issue 6, 2015, Pages 2584-2608

  Rankovic, Zoran ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CENTRAL NERVOUS SYSTEM AGENTS;

ACTIVE TRANSPORT; BLOOD BRAIN BARRIER; DRUG DESIGN; DRUG EXPOSURE; HYDROGEN BOND; IONIZATION; LIPOPHILICITY; MEDICINAL CHEMISTRY; MEMBRANE PERMEABILITY; MOLECULAR WEIGHT; NONHUMAN; PHYSICAL CHEMISTRY; REVIEW; SURFACE PROPERTY; ANIMAL; BRAIN; CHEMICAL STRUCTURE; CHEMISTRY; HUMAN; METABOLISM; PERMEABILITY;

ANIMALS; BIOLOGICAL TRANSPORT, ACTIVE; BLOOD-BRAIN BARRIER; BRAIN; CENTRAL NERVOUS SYSTEM AGENTS; DRUG DESIGN; HUMANS; MODELS, MOLECULAR; PERMEABILITY;

EID: 84925854124     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm501535r     Document Type: Review

References (158)

1. Chandler, D. J. Somethings got to give: psychiatric disease on the rise and novel drug development on the decline Drug Discovery Today 2013, 18, 202-206
2. Forecasting Health Care Costs; National Bureau of Economic Research: Cambridge, MA; http://www.nber.org/aginghealth/2008no4/w14361.html.
3. Barnholtz-Sloan, J. S.; Sloan, A. E.; Davis, F. G.; Vigneau, F. D.; Lai, P.; Sawaya, R. E. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the metropolitan detroit cancer surveillance system J. Clin. Oncol. 2004, 22, 2865-2872
4. Siegel, R.; Ma, J.; Zou, Z.; Jemal, A. Cancer statistics Cancer J. Clin. 2014, 64, 9-29 2014
5. Nguyen, T. D.; DeAngelis, L. M. Brain metastases Neurol. Clin. 2007, 25, 1173-1192
6. Johnson, T. W.; Richardson, P. F.; Bailey, S.; Brooun, A.; Burke, B. J.; Collins, M. R.; Cui, J. J.; Deal, J. G.; Deng, Y.-L.; Dinh, D.; Engstrom, L. D.; He, M.; Hoffman, J.; Hoffman, R. L.; Huang, Q.; Kania, R. S.; Kath, J. C.; Lam, H.; Lam, J. L.; Le, P. T.; Lingardo, L.; Liu, W.; McTigue, M.; Palmer, C. L.; Sach, N. W.; Smeal, T.; Smith, G. L.; Stewart, A. E.; Timofeevski, S.; Zhu, H.; Zhu, J.; Zou, H. Y.; Edwards, M. P. Discovery of (10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and cros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations J. Med. Chem. 2014, 57, 4720-4744
7. Pardridge, W. M. The blood-brain barrier: bottleneck in brain drug development NeuroRx 2005, 2, 3-14
8. Shen, D. D.; Artru, A. A.; Adkison, K. K. Principles and applicability of CSF sampling for the assessment of CNS drug delivery and pharmacodynamics Adv. Drug Delivery Rev. 2004, 56, 1825-1827
9. Martin, I. Prediction of blood-brain barrier penetration: are we missing the point? Drug Discovery Today 2004, 9, 161-162
10. Giacomini, K. M.; Huang, S.-M.; Tweedie, D. J.; Benet, L. Z.; Brouwer, K. L. R.; Chu, X.; Dahlin, A.; Evers, R.; Fischer, V.; Hillgren, K. M.; Hoffmaster, K. A.; Ishikawa, T.; Keppler, D.; Kim, R. B.; Lee, C. A.; Niemi, M.; Polli, J. W.; Sugiyama, Y.; Swaan, P. W.; Ware, J. A.; Wright, S. H.; Yee, S. W.; Zamek-Gliszczynski, M. J.; Zhang, L. Membrane transporters in drug development Nat. Rev. Drug Discovery 2010, 9, 215-236
11. Abbott, N. J.; Rönnbäck, L.; Hansson, L. Astrocyte-endothelial interactions at the blood-brain barrier Nat. Rev. Neurosci. 2006, 7, 41-53
12. Di, L.; Artursson, P.; Avdeef, A.; Ecker, G. F.; Faller, B.; Fischer, H.; Houston, J. B.; Kansy, M.; Kerns, E. H.; Kramer, S. D.; Lennernas, H.; Sugano, K. Evidence-based approach to assess passive diffusion and carrier-mediated drug transport Drug Discovery Today 2012, 17, 905-912
13. Rankovic, Z. Designing CNS drugs for optimal brain exposure. In Blood-Brain Barrier in Drug Discovery: Optimizing Brain Exposure of CNS Drugs and Minimizing Brain Side Effects, 1 st ed.; Di, L.; Kerns, E. H., Eds.; Wiley: New York, 2015.
14. Rankovic, Z.; Bingham, M. Medicinal chemistry challenges in CNS drug discovery. In Drug Discovery for Psychiatric Disorders, 1 st ed.; Rankovic, Z.; Bingham, M.; Nestler, E.; Hargreaves, R., Eds.; Royal Society of Chemistry: London, 2013; pp 465-509.
15. Hitchcock, S. A.; Pennington, L. D. Structure-brain exposure relationships J. Med. Chem. 2006, 49, 7559-7583
16. Malakoutikhah, M.; Teixid, M.; Giralt, E. Shuttle-mediated drug delivery to the brain Angew. Chem., Int. Ed. 2011, 50, 7998-8014
17. Liu, X.; Chen, C. Strategies to optimize brain penetration in drug discovery Curr. Opin. Drug Discovery Dev. 2005, 8, 505-512
18. 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.; Szewc, M. A.; Deusen, J. V. 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. Ther. 2005, 313, 1254-1262
19. Pardridge, W. M. Blood-brain barrier delivery Drug Discovery Today 2007, 12, 54-61
20. 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 Discovery 2007, 6, 50-661
21. 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
22. Markus, P.; Vernaleken, I.; Roesch, F. Positron emission tomography in CNS drug discovery and drug monitoring J. Med. Chem. 2014, 57, 9232-9258
23. Di, L.; Rong, H.; Feng, B. Demystifying brain penetration in central nervous system drug discovery J. Med. Chem. 2013, 56, 2-12
24. Wu, D.; Kang, Y.-S.; Bickel, U.; Pardridge, W. M. Blood-brain barrier permeability to morphine-6-glucuronide is markedly reduced compared with morphine Drug Metab. Dispos. 1997, 26, 768-771
25. Frolich, N.; Dees, C.; Paetz, C.; Ren, X.; Lohse, M. J.; Nikolaev, V. O.; Zenk, M. H. Distinct pharmacological properties of morphine metabolites at Gi-protein and β-arrestin signaling pathways activated by the human μ-opioid receptor Biochem. Pharmacol. 2011, 81, 1248-1254
26. Paul, D.; Standiffer, K. M.; Inturrisi, C. E.; Pasternak, G. W. Pharmacological characterization of morphine 6-b-glucuronidase, a very potent morphine metabolite J. Pharmacol. Exp. Ther. 1998, 251, 477-483
27. Reichel, A. Addressing central nervous system (CNS) penetration in drug discovery: Basics and implications of the evolving new concept Chem. Biodivers. 2009, 6, 2030-2049
28. Stain-Texier, F.; Boschi, G.; Sandouk, P.; Scherrmann, J. M. Elevated concentrations of morphine 6-beta- d -glucuronide in brain extracellular fluid despite low blood-brain barrier permeability Br. J. Pharmacol. 1999, 128, 917-924
29. Gupta, A.; Hammarlund-Udenaes, M.; Chatelain, P.; Massingham, R.; Jonsson, E. N. Stereoselective pharmacokinetics of cetirizine in the guinea pig: role of protein binding Biopharm. Drug Dispos. 2006, 27, 291-297
30. Smith, D. A.; Di, L.; Kerns, E. H. The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery Nat. Rev. Drug Discovery 2010, 9, 929-939
31. Polli, J. W.; Baughman, T. M.; Humphreys, J. E.; Jordan, K.H.; Mote, A. L.; Salisbury, J. A.; Tippin, T. K.; Serabjit-Singh, C. J. P-glycoprotein influences the brain concentrations of cetirizine (Zyrtec), a second-generation non-sedating antihistamine J. Pharm. Sci. 2003, 92, 2082-2089
32. Simon, F. E. R.; Simons, K. J. H1 antihistamines: current status and future directions World Allergy Organ. J. 2008, 1, 145-155
33. Sadiq, M. W.; 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
34. 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
35. 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.; 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
36. Hammarlund-Udenaes, M.; Friden; Syvnen, M. S.; Gupta, A. On the rate and extent of drug delivery to the brain Pharm. Res. 2008, 25, 1737-1750
37. Wang, X.; Ratnaraj, N.; Patsalos, P. N. The pharmacokinetic inter-relationship of tiagabine in blood, cerebrospinal fluid and brain extracellular fluid (frontal cortex and hippocampus) Seizure 2004, 13, 574-581
38. Friden, 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
39. Kodaira, H.; Kusuhara, H.; Fujita, T.; Ushiki, J.; Fuse, E.; Sugiyama, Y. Quantitative evaluation of the impact of active efflux by P-glycoprotein and breast cancer resistance protein at the blood-brain barrier on the predictability of the unbound concentrations of drugs in the brain using cerebrospinal fluid concentration as a surrogate J. Pharmacol. Exp. Ther. 2011, 339, 935-944
40. De Lange, E. C. M. Utility of CSF in translational neuroscience J. Pharmacokinet. Pharmacodyn. 2013, 40, 315-326
41. Westerhout, J.; Danhof, M.; De Lange, E. C. M. Preclinical prediction of human brain target site concentrations: Considerations and extrapolating to the clinical setting J. Pharm. Sci. 2011, 100, 3577-3593
42. Wan, H.; Rehngren, M.; Giordanetto, F.; Bergstrçm, F.; Tunek, A. High-throughput screening of drug-brain tissue binding and in silico prediction for assessment of central nervous system drug delivery J. Med. Chem. 2007, 50, 4606-4615
43. Friden, M.; Gupta, A.; Antonsson, M.; Bredberg, U.; Hammarlund-Udenaes, M. In vitro methods for estimating unbound drug concentrations in the brain interstitial and intracellular fluids Drug Metab. Dispos. 2007, 35, 1711-1719
44. Liu, X.; Natta, K.; van Yeo, H.; Vilenski, O.; Weller, P.; Worboys, P.; Monshouwer, M. Unbound drug concentration in brain homogenate and cerebral spinal fluid at steady state as a surrogate for unbound concentration in brain interstitial fluid Drug Metab. Dispos. 2009, 37, 787-793
45. Debruyne, D. Clinical pharmacokinetics of fluconazole in superficial and systemic mycoses Clin. Pharmacokinet. 1997, 33, 52-77
46. Summerfield, S. G.; Lucas, A. J.; Porter, R. A.; Jeffrey, P.; Gunn, R. N.; Read, K. R.; Stevens, A. J.; Metcalf, A. C.; Osuna, M. C.; Kilford, P. J.; Passchier, J.; Ruffo, A. D. Toward an improved prediction of human in vivo brain penetration Xenobiotica 2008, 38, 1518-1535
47. Di, L.; Umland, J. P.; Chang, G.; Huang, Y.; Lin, Z.; Scott, D. O.; Troutman, M. D.; Liston, T. E. Species independence in brain tissue binding using brain homogenates Drug Metab. Dispos. 2011, 39, 1270-1277
48. Jeffrey, P.; Summerfield, S. G. Challenges for blood-brain barrier (BBB) screening Xenobiotica 2007, 37, 1135-1151
49. Liu, X.; Wright, M.; Hop, C. E. C. A. Rational use of plasma protein and tissue binding data in drug design J. Med. Chem. 2014, 57, 8238-8248
50. 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.; Oeberg, J. O.; Oesterberg, T. In-vitro models for the blood brain barrier Toxicol. In Vitro 2005, 19, 299-334
51. Kansy, M.; Senner, F.; Gubernator, K. Physicochemical high throughput screening: parallel artificial membrane permeation assay in the description of passive absorption processes J. Med. Chem. 1998, 41, 1007-1010
52. Veber, D. F.; Johnson, S. R.; Chen, H.-Y.; Smith, B. R.; Ward, K. W.; Kopple, K. D. Molecular properties that influence the oral bioavailability of drug candidates J. Med. Chem. 2002, 45, 2615-2623
53. Giacomini, K. M.; Huang, S.-M.; Tweedie, D. J.; Benet, L. Z.; Brouwer, K. L. R.; Chu, X.; Dahlin, A.; Evers, R.; Fischer, V.; Hillgren, K. M.; Hoffmaster, K. A.; Ishikawa, T.; Keppler, D.; Kim, R. B.; Lee, C. A.; Niemi, M.; Polli, J. W.; Sugiyama, Y.; Swaan, P. W.; Ware, J. A.; Wright, S. H.; Yee, S. W.; Zamek-Gliszczynski, M. J.; Zhang, L. Membrane transporters in drug development Nat. Rev. Drug Discovery 2010, 9, 215-236
54. Hitchcock, S. A. Structural modifications that alter the P-glycoprotein efflux properties of compounds J. Med. Chem. 2012, 55, 4877-4895
55. Sharom, F. J. The P-glycoprotein efflux pump: how does it transport drugs? J. Membr. Biol. 1997, 160, 161-175
56. Cordon-Cardo, C.; OBrien, J. P.; Casals, D.; Rittman-Grauer, L.; Biedler, J. L.; Melamed, M. R.; Bertino, J. R. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 695-698
57. Doan, M. K. M.; Humphreys, J. E.; Webster, L. O.; Wring, S. A.; Shampine, L. J.; Serabjit-Singh, C. J.; Adkinson, 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
58. Demeule, M.; Regina, A.; Jodoin, J.; Laplante, A.; Dagenais, C.; Berthelet, F.; Moghrabi, A.; Beliveau, R. Drug transport to the brain: Key roles for the efflux pump P-glycoprotein in the blood-brain barrier Vasc. Pharmacol. 2002, 38, 339-348
59. Feng, B.; Mills, J. B.; Davidson, R. E.; Mireles, R. J.; Janiszewski, J. S.; Troutman, M. D.; de Morais, S. M. In vitro P-glycoprotein assays to predict the in vivo interactions of P-glycoprotein with drugs in the central nervous system Drug Metab. Dispos. 2008, 36, 268-275
60. Hsiao, P.; Sasongko, L.; Link, J. M.; Mankoff, D. A.; Muzi, M.; Collier, A. C.; Unadkat, J. D. Verapamil P-glycoprotein transport across the rat blood-brain barrier: cyclosporine, a concentration inhibition analysis, and comparison with human data J. Pharmacol. Exp. Ther. 2006, 317, 704-710
61. 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. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding Science 2009, 323, 1718-1722
62. Desai, P. V.; Raub, T. J.; Blanco, M.-J. How hydrogen bonds impact P-glycoprotein transport and permeability Bioorg. Med. Chem. Lett. 2012, 22, 6540-6548
63. Raub, T. J.; Lutzke, B. S.; Andrus, P. K.; Sawada, G. A.; Staton, B. A. Early preclinical evaluation of brain exposure in support of hit identification and lead optimization. In Optimizing the Drug-Like Properties of Leads in Drug Discovery, 1 st ed.; Borchardt, R. T.; Kerns, E. H.; Hageman, M. J.; Thakker, D. R.; Stevens, J. L., Eds.; Springer: New York, 2006; pp 355-410.
64. Doyle, L. A.; Yang, W.; Abruzzo, L. V.; Krogmann, T.; Gao, Y.; Rishi, A. K.; Ross, D. D. A multidrug resistance transporter from human MCF-7 breast cancer cells Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 15665-15670
65. Eisenblatter, T.; Galla, H. J. A new multidrug resistance protein at the blood-brain barrier Biochem. Biophys. Res. Commun. 2002, 293, 1273-1278
66. Chen, Y.; Agarwal, S.; Shaik, N. M.; Chen, C.; Yang, Z.; Elmquist, W. F. P-glycoprotein and breast cancer resistance protein influence brain distribution of dasatinib J. Pharmacol. Exp. Ther. 2009, 330, 956-63
67. Tang, S. C.; Lagas, J. C.; Lankheet, N. A. G.; Poller, B.; Hillebrand, M. J.; Rosing, H.; Beijnen, J. H.; Schinkel, A. H. Brain accumulation of sunitinib is restricted by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and can be enhanced by oral elacridar and sunitinib coadministration Int. J. Cancer 2012, 130, 223-233
68. Zhao, R.; Raub, T. J.; Sawada, G. A.; Kasper, S. C.; Bacon, J. A.; Bridges, A. S.; Pollack, G. M. Breast cancer resistance protein interacts with various compounds in vitro, but plays a minor role in substrate efflux at the blood-brain barrier Drug Metab. Dispos. 2009, 37, 1251-1258
69. Giri, N.; Shaik, N.; Pan, G.; Terasaki, T.; Mukai, C.; Kitagaki, S.; Miyakoshi, N.; Elmquist, W. F. Investigation of the role of breast cancer resistance protein (Bcrp/Abcg2) on pharmacokinetics and central nervous system penetration of abacavir and zidovudine in the mouse Drug. Metab. Dispos. 2008, 36, 1476-1484
70. Ball, K.; Bouzom, F.; Scherrmann, J.-M.; Walther, B.; Decleves, X. Physiologically based pharmacokinetic modelling of drug penetration across the blood-brain barrier-Towards a mechanistic IVIVE-based approach AAPS J. 2013, 15, 913-932
71. Ball, K.; Bouzom, F.; Scherrmann, J.-M.; Walther, B.; Decleves, X. Development of a physiologically based pharmacokinetic model for the rat central nervous system and determination of an in vitro-in vivo scaling methodology for the blood-brain barrier permeability of two transporter substrates, morphine and oxycodone J. Pharm. Sci. 2012, 101, 4277-4292
72. Eyal, S.; Hsiao, P.; Unadkat, J. D. Drug interactions at the blood-brain barrier: fact or fantasy? Pharmacol. Ther. 2009, 123, 80-104
73. Kalvass, J. C.; Polli, J. W.; Bourdet, D. L.; Feng, B.; Huang, S.-M.; Liu, X.; Smith, Q. R.; Zhang, L. K.; Zamek-Gliszczynski, M. J. Why clinical modulation of efflux transport at the human blood-brain barrier is unlikely: the ITC evidence-based position Clin. Pharmacol. Ther. 2013, 94, 80-94
74. Schinkel, A. H.; Mayer, U.; Wagenaar, E.; Mol, C. A. A. M.; van Deemter, L.; Smit, J. J. M.; van der Valk, M. A.; Voordouw, A. C.; Spits, H.; van Tellingen, O.; Zijlmans, J. M.; Fibbe, W. E.; Borst, P. Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 4028-4033
75. Cutler, L.; Howes, C.; Deeks, N. J.; Buck, T. L.; Jeffrey, P. Development of a P-glycoprotein knockout model in rodents to define species differences in its functional effect at the blood-brain barrier J. Pharm. Sci. 2006, 95, 1944-1953
76. Syvanen, S.; Lindhe, O.; Palner, M.; Kornum, B. R.; Rahman, O.; Langstrom, B.; Knudsen, G. M.; Hammarlund-Udenaes, M. Species differences in blood-brain barrier transport of three positron emission tomography radioligands with emphasis on P-glycoprotein transport Drug Metab. Dispos. 2009, 37, 635-643
77. Desai, P. V.; Sawada, G. A.; Watson, I. A.; Raub, T. J. Integration of in silico and in vitro tools for scaffold optimization during drug discovery: predicting P-glycoprotein efflux Mol. Pharmaceutics 2013, 10, 1249-1261
78. Didziapetris, R.; Japertas, P.; Avdeef, A.; Petrauskas, A. Classification analysis of P-glycoprotein substrate specificity J. Drug Targeting 2003, 11, 391-406
79. Del Amo, E. M.; Urtti, A.; Yliperttula, M. Pharmacokinetic role of L-type amino acid transporters LAT1 and LAT2 Eur. J. Pharm. Sci. 2008, 35, 161-174
80. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings Adv. Drug Del. Rev. 1997, 23, 3-26
81. Ghose, A. K.; Herbertz, T.; Hudkins, R. L.; Dorsey, B. D.; Mallamo, J. P. Knowledge-based, central nervous system (CNS) lead selection and lead optimization for CNS drug discovery ACS Chem. Neurosci. 2012, 3, 50-68
82. Wager, T. T.; Chandrasekaran, R. Y.; Hou, X.; Troutman, M. D.; Verhoest, P. R.; 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
83. Wager, T. T.; Hou, X.; Verhoest, P. R.; 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
84. Waring, M. J. Defining optimum lipophilicity and molecular weight ranges for drug candidates-molecular weight dependent lower logD limits based on permeability Bioorg. Med. Chem. Lett. 2009, 19, 2844-2851
85. Gleeson, M. P. Generation of a set of simple, interpretable ADMET rules of thumb J. Med. Chem. 2008, 51, 817-834
86. Pajouhesh, H.; Lenz, G. R. Medicinal chemical properties of successful central nervous system drugs NeuroRx 2005, 2, 541-553
87. Leeson, P. D.; Davis, A. M. Time-related differences in the physical property profiles of oral drugs J. Med. Chem. 2004, 47, 6338-6348
88. Norinder, U.; Haeberlein, M. Computational approaches to the prediction of the blood-brain distribution Adv. Drug Deliv. Rev. 2002, 54, 291-313
89. Kelder, J.; Grootenhuis, P. D. J.; Bayada, D. M.; Delbressine, L. P. C.; Ploemen, J.-P. Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs Pharm. Res. 1999, 16, 1514-1519
90. 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
91. Van de Waterbeemd, H.; Kansy, M. Hydrogen-bonding capacity and brain penetration Chimia 1992, 46, 299-303
92. 2 receptor histamine antagonists J. Med. Chem. 1988, 31, 656-671
93. Hansch, C.; Steward, A. R.; Anderson, S. M.; Bentley, D. L. Parabolic dependence of drug action upon lipophilic character as revealed by a study of hypnotics J. Med. Chem. 1968, 1, 1-11
94. Leeson, P. D.; Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry Nat. Rev. Drug Discovery 2007, 6, 881-890
95. Leo, A.; Hansch, C.; Elkins, D. Partition coefficients and their uses Chem. Rev. 1971, 71, 525-616
96. Johnson, D. J.; Forbes, I. T.; Watson, S. P.; Garzya, V.; Stevenson, G. I.; Walker, G. R.; Mudhar, H. S.; Flynn, S. J.; Wyman, P. A.; Smith, P. W.; Murkitt, G. S.; Lucas, A. J.; Mookherjee, C. R.; Watson, J. M.; Gartlon, J. E.; Bradford, A. M.; 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
97. Smith, P. W.; Wyman, P. A.; Lovell, P.; Goodacre, C.; Serafinowska, H. T.; Vong, A.; Harrington, F.; Flynn, S.; Bradley, D. M.; Porter, R.; Coggon, S.; Murkitt, G.; Searle, K.; Thomas, D. R.; Watson, J. M.; Martin, W.; Wu, Z.; Dawson, L. A. New quinoline NK3 receptor antagonists with CNS activity Bioorg. Med. Chem. Lett. 2009, 19, 837-840
98. Martin, Y. C. A bioavailability score J. Med. Chem. 2005, 48, 3164-3170
99. Abraham, M. H. Scales of solute hydrogen-bonding: their construction and application to physicochemical and biochemical processes Chem. Soc. Rev. 1993, 22, 73-83
100. Kuduk, S. D.; Di Marco, C. N.; Chang, R. K.; Wood, M. R.; Schirripa, K. M.; Kim, J. J.; Wai, J. M.; DiPardo, R. M.; Murphy, K. L.; Ransom, R. W.; Harrell, C. M.; Reiss, D. R.; Holahan, M. A.; Cook, J.; Hess, J. F.; Sain, N.; Urban, M. O.; Tang, C.; Prueksaritanont, T.; Pettibone, D. J.; Bock, M. G. Development of orally bioavailable and CNS penetrant biphenylaminocyclopropane carboxamide bradykinin B1 receptor antagonists J. Med. Chem. 2007, 50, 272-282
101. Hu, E.; Kunz, R. K.; 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, J. R. 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
102. Kuhn, B.; Mohr, P.; Stahl, M. Intramolecular hydrogen bonding in medicinal chemistry J. Med. Chem. 2010, 53, 2601-2611
103. Rafi, S. B.; Hearn, B. R.; Vedantham, P.; Jacobson, M. P.; Renslo, A. R. Predicting and improving the membrane permeability of peptidic small molecules J. Med. Chem. 2012, 55, 3163-3169
104. Ashwood, V. A.; Field, M. J.; Horwell, D. C.; Julien-Larose, C.; Lewthwaite, R. A.; McCleary, S.; Pritchard, M. C.; 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
105. Over, B.; McCarren, P.; Artursson, P.; Foley, M.; Giordanetto, F.; Grönberg, G.; Hilgendorf, C.; Lee, M. D.; Matsson, P.; Muncipinto, G.; Pellisson, M.; Perry, M. W. D.; Svensson, R.; Duvall, J. R.; Kihlberg, J. Impact of stereospecific intramolecular hydrogen bonding on cell permeability and physicochemical properties J. Med. Chem. 2014, 57, 2746-2754
106. Hennig, L.; Ayala-Leon, K.; Angulo-Cornejo, J.; Richter, R.; Beyer, L. Fluorine hydrogen short contacts and hydrogen bonds in substituted benzamides J. Fluorine Chem. 2009, 130, 453-460
107. Weiss, M. M.; Williamson, T.; Babu-Khan, S.; Bartberger, M. D.; Brown, J.; Chen, K.; Cheng, Y.; Citron, M.; Croghan, M. D.; Dineen, T. A.; Esmay, J.; Graceffa, R. F.; Harried, S. S.; Hickman, D.; Hitchcock, S. A.; Horne, D. B.; Huang, H.; Imbeah-Ampiah, R.; Judd, T.; Kaller, M. R.; Kreiman, C. R.; La, D. S.; Li, V.; Lopez, P.; Louie, S.; Monenschein, H.; Nguyen, T. T.; Pennington, L. D.; Rattan, C.; San Miguel, T.; Sickmier, E. A.; Wahl, R. C.; Wen, P. H.; Wood, S.; Xue, Q.; Yang, B. H.; Patel, V. F.; Zhong, W. Design and preparation of a potent series of hydroxyethylamine containing β-secretase inhibitors that demonstrate robust reduction of central β-amyloid J. Med. Chem. 2012, 55, 9009-9024
108. Yuan, J.; Venkatraman, S.; Zheng, Y.; McKeever, B. M.; Dillard, L. W.; Singh, S. B. Structure-based design of β-site APP cleaving enzyme 1 (BACE1) inhibitors for the treatment of Alzheimers disease J. Med. Chem. 2013, 56, 4156-4180
109. Alex, A.; Millan, D. S.; Perez, M.; Wakenhut, F.; Whitlock, G. A. Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space Med. Chem. Commun. 2011, 2, 669-674
110. 1H chemical shifts in proteins J. Biomol. NMR 1997, 9, 359-369
111. Tardia, P.; Stefanachi, A.; Niso, M.; Stolfa, D. A.; Mangiatordi, G. F.; DAlberga, D.; Nicolotti, O.; Lattanzi, G.; Carotti, A.; Leonetti, F.; Perrone, R.; Berardi, F.; Azzariti, A.; Colabufo, N. A.; Cellamare, S. Trimethoxybenzanilide-based P-glycoprotein modulators: an interesting case of lipophilicity tuning by intramolecular hydrogen bonding J. Med. Chem. 2014, 57, 6403-6418
112. Shalaeva, M.; Caron, G.; Abramov, Y. A.; OConnell, T. N.; Plummer, M. S.; Yalamanchi, G.; Farley, K. A.; Goetz, G. H.; Philippe, L.; Shapiro, M. J. Integrating intramolecular hydrogen bonding (IMHB) considerations in drug discovery using ΔlogP as a tool J. Med. Chem. 2013, 56, 4870-4879
113. Goetz, H.; Farrell, W.; Shalaeva, M.; Sciabola, S.; Anderson, D.; Yan, J.; Philippe, L.; Shapiro, M. J. High throughput method for the indirect detection of intramolecular hydrogen bonding J. Med. Chem. 2014, 57, 2920-2929
114. Ertl, P.; Rohde, B.; Selzer, P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties J. Med. Chem. 2000, 43, 3714-3717
115. Palm, K.; Luthman, K.; Ungell, A. L.; Strandlund, G.; Artursson, P. Correlation of drug absorption with molecular surface properties J. Pharm. Sci. 1996, 85, 32-39
116. Richmond, T. J. T. Solvent accessible surface area and excluded volume in proteins J. Mol. Biol. 1984, 178, 63-89
117. Goldberg, F. W.; Dossetter, A. G.; Scott, J. S.; Robb, R.; Boyd, S.; Groombridge, S. D.; Kemmitt, P. D.; Sjogren, T.; Gutierrez, P. M.; De Schoolmeester, J.; Swales, J. G.; Turnbull, A. W.; Wild, M. J. Optimization of brain penetrant 11β-hydroxysteroid dehydrogenase type I inhibitors and in vivo testing in diet-induced obese mice J. Med. Chem. 2014, 57, 970-986
118. Ward, S. E.; Harries, M.; Aldegheri, L.; Andreotti, D.; Ballantine, S.; Bax, B. D.; Harris, A. J.; Harker, A. J.; Lund, J.; Melarange, R.; Mingardi, A.; Mookherjee, C.; Mosley, J.; Neve, M.; Oliosi, B.; Profeta, R.; Smith, K. J.; Smith, P. W.; Spada, S.; Thewlis, K. M.; Yusaf, S. P. Discovery of N -[(2S)-5-(6-fluoro-3-pyridinyl)-2,3-dihydro-1 H -inden-2-yl]-2-propanesulfonamide, a novel clinical AMPA receptor positive modulator J. Med. Chem. 2010, 53, 5801-5812
119. McDonald, I. M.; Mate, R. A.; Zusi, F. C.; Huang, H.; Post-Munson, D. J.; Ferrante, M. A.; Gallagher, L.; Bertekap, R. L., Jr.; Knox, R. J.; Robertson, B. J.; Harden, D. G.; Morgan, D. G.; Lodge, N. J.; Dworetzky, S. I.; Olson, R. E.; Macor, J. E. Discovery of a novel series of quinolone α7 nicotinic acetylcholine receptor agonists Bioorg. Med. Chem. Lett. 2013, 23, 1684-1688
120. 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
121. Rampe, D.; Wible, B.; Brown, A. M.; Dage, R. C. Effects of terfenadine and its metabolites on a delayed rectifier K1 channel cloned from human heart Mol. Pharmacol. 1993, 44, 1240-1245
122. Doan, M. K. M.; Wring, S. A.; Shampine, L. J.; Jordan, K. H.; Bishop, J. P.; Kratz, J.; Yang, E.; Serabjit-Singh, C. J.; Adkison, K. K.; Polli, J. W. Steady-state brain concentrations of antihistamines in rats: interplay of membrane permeability, P-glycoprotein efflux and plasma protein binding Pharmacology 2004, 72, 92-98
123. Zhao, R.; Kalvass, J. C.; Yanni, S. B.; Bridges, A. S.; Pollack, G. M. Fexofenadine brain exposure and the influence of blood-brain barrier P-glycoprotein after fexofenadine and terfenadine administration Drug Metab. Dispos. 2009, 37, 529-535
124. Mihalic, J. T.; 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
125. Hogberg, T.; Frimurer, T.; Sasmal, P. K. Melanin concentrating hormone receptor 1 (MCHR1) antagonists-still a viable approach for obesity treatment? Bioorg. Med. Chem. Lett. 2012, 22, 6039-6047
126. Jamieson, C.; Moir, E. M.; Rankovic, Z.; Wishart, G. Medicinal chemistry of hERG optimizations: highlights and hang-ups J. Med. Chem. 2006, 49, 5029-5050
127. Gianotti, M.; Botta, M.; Brough, S.; Carletti, R.; Castiglioni, E.; Corti, C.; Dal-Cin, M.; Fratte, S. D.; 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, M. J. Novel spirotetracyclic zwitterionic dual H1/5-HT2A receptor antagonists for the treatment of sleep disorders J. Med. Chem. 2010, 53, 7778-7795
128. McCoull, W.; Barton, P.; Brown, A. J. H.; Bowker, S. S.; Cameron, J.; Clarke, D. S.; Davies, R. D. M.; Dossetter, A. G.; Ertan, A.; Fenwick, M.; Green, C.; Holmes, J. L.; Martin, N.; Masters, D.; Moore, J. E.; Newcombe, N. J.; Newton, C.; Pointon, H.; Robb, G. R.; Sheldon, C.; Stokes, S.; Morgan, D. Identification, optimization, and pharmacology of acylurea GHS-R1a inverse agonists J. Med. Chem. 2014, 57, 6128-6140
129. Costa, D. B.; Kobayashi, S.; Pandya, S. S.; Yeo, W. L.; Shen, Z.; Tan, W.; Wilner, K. D. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib J. Clin. Oncol. 2011, 29, 443-445
130. Marsault, E.; Peterson, M. L. Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery J. Med. Chem. 2011, 54, 1961-2004
131. Levin, V. A. Relationship of octanol/water partition coefficients to rat brain capillary permeability J. Med. Chem. 1980, 23, 682-684
132. Hopkins, A. L.; Groom, C. R.; Alex, A. Ligand efficiency: a useful metric for lead selection Drug Discovery Today 2004, 9, 430-431
133. Bergstrom, C. A. S.; 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
134. Tantishaiyakul, V. Prediction of Caco-2 cell permeability using partial least square multivariate analysis Pharmazie 2001, 56, 407-411
135. Egan, W. J.; Merz, K. M., Jr.; Baldwin, J. J. Prediction of drug absorption using multivariate statistics J. Med. Chem. 2000, 43, 3867-3877
136. Keseru, G. M.; Makara, G. M. The influence of lead discovery strategies on the properties of drug candidates Nat. Rev. Drug Discovery 2009, 8, 203-212
137. Tarcsay, A.; Nyiri, K.; Keseru, G. M. Impact of lipophilic efficiency on compound quality J. Med. Chem. 2012, 55, 1252-1260
138. Nicolaou, C. A.; Brown, N. Multi-objective optimization methods in drug design Drug Discovery Today: Technol. 2013, 10, 427-435
139. Shen, J.; Cheng, F.; Xu, Y.; Li, W.; Tang, Y. Estimation of ADME properties with substructure pattern recognition J. Chem. Inf. Model. 2010, 50, 1034-1041
140. 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
141. Need, A. B.; McKinzie, J. H.; Mitch, C. H.; Statnick, M. A.; Phebus, L. A. In vivo rat brain opioid receptor binding of LY255582 assessed with a novel method using LC/MS/MS and the administration of three tracers simultaneously Life Sci. 2007, 81, 1389-1396
142. Hawkins, B. T.; Davis, T. P. The blood-brain barrier/neurovascular unit in health and disease Am. Soc. Pharmacol. Exp. Ther. 2005, 57, 173-185
143. Seelbach, M. J.; Brooks, T. A.; Egleton, R. D.; Davis, T. P. Peripheral inflammatory hyperalgesia modulates morphine delivery to the brain: a role for P-glycoprotein J. Neurochem. 2007, 102, 1677-1690
144. Vieth, M.; Siegel, M. G.; Higgs, R. E.; Watson, I. A.; Robertson, D. H.; Savin, K. A.; Durst, G. L.; Hipskind, P. A. Characteristic physical properties and structural fragments of marketed oral drugs J. Med. Chem. 2004, 47, 224-232
145. Morphy, R. The influence of target family and functional activity on the physicochemical properties of pre-clinical compounds J. Med. Chem. 2006, 49, 2969-2978
146. Hughes, J. D.; Blagg, J.; Price, D. A.; Bailey, S.; DeCrescenzo, G. A.; Ellsworth, R. V. D. E.; Fobian, Y. M.; Gibbs, M. E.; Gilles, R. W.; Greene, N.; Krieger-Burke, E. H. T.; Loesel, J.; Wager, T.; Whiteley, L.; Zhang, Y. Physiochemical drug properties associated with in vivo toxicological outcomes Bioorg. Med. Chem. Lett. 2008, 18, 4872-4875
147. Lovering, F.; Bikker, J.; Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success J. Med. Chem. 2009, 52, 6752-6756
148. Ritchie1, T. J.; Macdonald, S. J. F.; Young, R. J.; Pickett, S. D. The impact of aromatic ring count on compound developability: further insights by examining carbo- and hetero-aromatic and -aliphatic ring types Drug Discovery Today 2011, 16, 164-171
149. Alelyunas, Y. W.; Empfield, J. R.; McCarthy, D.; Spreen, R. C.; Bui, K.; Pelosi-Kilby, L.; Shen, C. Experimental solubility profiling of marketed CNS drugs, exploring solubility limit of CNS discovery candidate Bioorg. Med. Chem. Lett. 2010, 20, 7312-7316
150. Noe, M. C.; Gilbert, A. M. Targeted covalent enzyme inhibitors Annu. Rep. Med. Chem. 2012, 47, 413-439
151. Dounay, A. B.; Anderson, M.; Bechle, B. M.; Campbell, B. M.; Claffey, M. M.; Evdokimov, A.; Evrard, E.; Fonseca, K. R.; Gan, X.; Ghosh, S.; Hayward, M. M.; Horner, W.; Kim, J.-Y.; McAllister, L. A.; Pandit, J.; Paradis, V.; Parikh, V. D.; Reese, M. R.; Rong, S.; Salafia, M. A.; Schuyten, K.; Strick, C. A.; Tuttle, J. B.; Valentine, J.; Wang, H.; Zawadzke, L. E.; Verhoest, P. R. Discovery of brain-penetrant, irreversible kynurenine aminotransferase II inhibitors for schizophrenia ACS Med. Chem. Lett. 2012, 3, 187-192
152. Johnson, D. S.; Stiff, C.; Lazerwith, S. E.; Kesten, S. R.; Fay, L. K.; Morris, M.; Beidler, D.; Liimatta, M. B.; Smith, S. E.; Dudley, D. T.; Sadagopan, N.; Bhattachar, S. N.; Kesten, S. J.; Nomanbhoy, T. K.; Cravatt, B. F.; Ahn, K. Discovery of PF-04457845: a highly potent, orally bioavailable, and selective urea FAAH inhibitor ACS Med. Chem. Lett. 2011, 2, 91-96
153. Potashman, M. H.; Duggan, M. E. Covalent modifiers: an orthogonal approach to drug design J. Med. Chem. 2009, 52, 1231-1246
154. Moghaddam, M. F.; Tang, Y.; OBrien, Z.; Richardson, S. J.; Bacold, M.; Chaturvedi, P.; Apuy, J.; Kulkarni, A. A proposed screening paradigm for discovery of covalent inhibitor drugs Drug Metab. Lett. 2014, 8, 19-30
155. Johansson, M. H. Reversible michael additions: covalent inhibitors and prodrugs Mini-Rev. Med. Chem. 2012, 12, 1330-1344
156. Uetrecht, J. P. New concepts in immunology relevant to idiosyncratic drug reactions: the ";danger hypothesis"; and innate immune system Chem. Res. Toxicol. 1999, 12, 387-395
157. Nakayama, S.; Atsumi, R.; Takakusa, H.; Kobayashi, Y.; Kurihara, A.; Nagai, Y.; Nakai, D.; Okazaki, O. A zone classification system for risk assessment of idiosyncratic drug toxicity using daily dose and covalent binding Drug Metab. Dispos. 2009, 37, 1970-1977
158. Regina, A.; Demeule, M.; Che, C.; Lavallee, I.; Poirier, J.; Gabathuler, R.; Beliveau, R.; Castaigne, J. P. Antitumour activity of ANG1005, a conjugate between paclitaxel and the new brain delivery vector Angiopep-2 Br. J. Pharmacol. 2008, 155, 185-197