Lipophilicity and Other Parameters Affecting Brain Penetration

Atkinson, F; Cole, Susan; Laverty, Caroline Elizabeth; Waterbeemd, H. Van De

doi:10.2174/1568015023358058

Cited by 52 publications

(46 citation statements)

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“…[56] In addition, TFAHs 10 l and 10 n present high TPSA values. According to the computed values of brain penetration, [57] TFAHs 10 a, 10 b, 10 c, and 10 f should be the best candidates of the series to act as CNS-active compounds.…”

Section: In Silico Admet Analysismentioning

confidence: 97%

Novel Tacrine‐Grafted Ugi Adducts as Multipotent Anti‐Alzheimer Drugs: A Synthetic Renewal in Tacrine–Ferulic Acid Hybrids

et al. 2014

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Herein we describe the design, multicomponent synthesis, and biological, molecular modeling and ADMET studies, as well as in vitro PAMPA-blood-brain barrier (BBB) analysis of new tacrine-ferulic acid hybrids (TFAHs). We identified (E)-3-(hydroxy-3-methoxyphenyl)-N-{8[(7-methoxy-1,2,3,4-tetrahydroacridin-9-yl)amino]octyl}-N-[2-(naphthalen-2-ylamino)2-oxoethyl]acrylamide (TFAH 10 n) as a particularly interesting multipotent compound that shows moderate and completely selective inhibition of human butyrylcholinesterase (IC50 =68.2 nM), strong antioxidant activity (4.29 equiv trolox in an oxygen radical absorbance capacity (ORAC) assay), and good β-amyloid (Aβ) anti-aggregation properties (65.6 % at 1:1 ratio); moreover, it is able to permeate central nervous system (CNS) tissues, as determined by PAMPA-BBB assay. Notably, even when tested at very high concentrations, TFAH 10 n easily surpasses the other TFAHs in hepatotoxicity profiling (59.4 % cell viability at 1000 μM), affording good neuroprotection against toxic insults such as Aβ1-40 , Aβ1-42 , H2 O2 , and oligomycin A/rotenone on SH-SY5Y cells, at 1 μM. The results reported herein support the development of new multipotent TFAH derivatives as potential drugs for the treatment of Alzheimer's disease.

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Section: In Silico Admet Analysismentioning

confidence: 97%

Novel Tacrine‐Grafted Ugi Adducts as Multipotent Anti‐Alzheimer Drugs: A Synthetic Renewal in Tacrine–Ferulic Acid Hybrids

et al. 2014

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“…The generally accepted biophysical/physicochemical models of BBB permeability have as their primary determinants for passive transport the solute's lipophilicity, hydrogen-bond desolvation potential, pK a /charge, and molecular size (Levin, 1980;Young et al, 1988;Jezequel, 1992;Chikhale et al, 1994;Atkinson et al, 2002;Abraham, 2004). Such models must, however, also acknowledge the potential for active mechanisms, which generally depend upon some specificity of molecular recognition and solute concentration at the transporter.…”

Section: Determinants Of Bbb Penetrationmentioning

confidence: 99%

“…There is, however, little room for complacency, especially given some recent high-profile criticism leveled at log BB as an index of brain penetration (Martin, 2004;Pardridge, 2004). In particular, the fact that log BB reflects the total drug concentration in the brain rather than the free drug concentration, which crucially determines the receptor saturation by the drug, has been highlighted (Atkinson et al, 2002). Pardridge (2004) contends that the best index of BBB permeability is the BBB PS product, because this can predict the level of free drug in the brain.…”

Section: The State Of the Artmentioning

confidence: 99%

“…For example, scientists at AstraZeneca, citing a log BB modeling paper (Clark, 1999), have described their efforts to produce a non-CNS penetrating -opioid receptor agonist by adding polar substituents to increase the PSA and reduce lipophilicity (Semple et al, 2003). Conversely, scientists at Neurogen have reported the results of lipophilicity and PSA calculations as evidence that a series of corticotrophin-releasing factor-1 receptor antagonists was likely to permeate the BBB (Hodgetts et al, 2003), again citing a review of predictive modeling (Atkinson et al, 2002) as their justification. Finally, the VolSurf BBB permeation model (Cruciani et al, 2000) has been employed recently to predict the BBB permeability of some prodrugs of nonsteroidal antiinflammatory agents (Perioli et al, 2004).…”

Section: Some Success Storiesmentioning

confidence: 99%

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In Silico Predictions of Blood-Brain Barrier Penetration: Considerations to “Keep in Mind”

Goodwin¹,

Clark²

2005

J Pharmacol Exp Ther

109

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Within drug discovery, it is desirable to determine whether a compound will penetrate and distribute within the central nervous system (CNS) with the requisite pharmacokinetic and pharmacodynamic performance required for a CNS target or if it will be excluded from the CNS, wherein potential toxicities would mitigate its applicability. A variety of in vivo and in vitro methods for assessing CNS penetration have therefore been developed and applied to advancing drug candidates with the desired properties. In silico methods to predict CNS penetration from chemical structures have been developed to address virtual screening and prospective design. In silico predictive methods are impacted by the quality, quantity, sources, and generation of the measured data available for model development. Key considerations for predictions of CNS penetration include the comparison of local (in chemistry space) versus global (more structurally diverse) models and where in the drug discovery process such models may be best deployed. Preference should also be given to in vitro and in vivo measurements of greater mechanistic clarity that better support the development of structure-property relationships. Although there are numerous statistical methods that have been brought to bear on the prediction of CNS penetration, a greater concern is that such models are appropriate for the quality of measured data available and are statistically validated. In addition, the assessment of prediction uncertainty and relevance of predictive models to structures of interest are critical. This article will address these key considerations for the development and application of in silico methods in drug discovery.The main interfaces between the central nervous system (CNS) and the peripheral circulation are the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier. The surface area of the former (approximately 20 m 2 ) is several thousand times larger than the latter; thus, the BBB represents the most important barrier between the CNS and the systemic circulation (Pardridge, 2002;Graff and Pollack, 2004). There are at least two aspects of the BBB that make it a formidable barrier to candidate CNS drugs. First, in terms of its morphology, the endothelial cells of which the BBB is composed are connected by complex tight junctions, which severely limit any paracellular transport. Furthermore, a minimal level of pinocytosis and lack of significant membrane fenestrae affords an additional hindrance to the transport of hydrophilic molecules. Second, the BBB includes an array of metabolic enzyme systems and efflux transporters that constitutes a biochemical barrier to the majority of xenobiotics (de Boer et al., 2003). This combination of physical and biochemical barriers establishes the BBB endothelium as quite distinct from other endothelia, and it has been estimated to prevent the brain uptake of more than 98% of potential neurotherapeutics (Pardridge, 2002).

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“…One of the best physicochemical indicators of diffusion within the CNS is the octanol/water partition coefficient (log P; ref. 63,64). The optimal log P for drugs designed to target the CNS should be ϳ2 (61, 62).…”

Section: Boron Containing Nucleosides As Delivery Agents For Nctmentioning

confidence: 99%

Boron-Containing Nucleosides as Potential Delivery Agents for Neutron Capture Therapy of Brain Tumors

Barth¹,

Yang²,

Madhoun³

et al. 2004

Cancer Research

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The purpose of the present study was to evaluate both in vitro and in vivo a series of boron-containing nucleosides that potentially could be used as delivery agents for neutron capture therapy. The rationale for their synthesis was based on the fact that proliferating neoplastic cells have increased requirements for nucleic acid precursors, and, therefore, they should preferentially localize in the tumor. A series of 3-carboranlyalkyl thymidine analogs has been synthesized and a subset, designated N4, N5, and N7, and the corresponding 3-dihydroxypropyl derivatives, designated N4 -2OH, N5-2OH, and N7-2OH, have been selected for evaluation. Using these compounds as substrates for recombinant human thymidine kinase-1 and the mitochondrial isoenzyme thymidine kinase-2, the highest phosphorylation levels relative to thymidine were seen with N5 and the corresponding dihydroxypropyl analog N5-2OH. In contrast, N4, N4-OH, N7, and N7-OH had substantially lower phosphorylation levels. To compare compounds with high and low thymidine kinase-1 substrate activity, N5 and N7 and the corresponding dihydroxypropyl derivatives were selected for evaluation of their cellular toxicity, uptake and retention by the F98 rat glioma, human MRA melanoma, and murine L929 cell lines, all of which are thymidine kinase-1(؉), and a mutant L929 cell line that is thymidine kinase-1(؊). N5-2OH was the least toxic (IC 50 , 43-70 M), and N7 and N7-2OH were the most toxic (IC 50 , 18 -49 M). The highest boron uptake was seen with N7-2OH by the MRA 27 melanoma and L929 wild-type (wt) cell lines. The highest retention was seen with L929 (wt) cells, and this ranged from 29% for N5-2OH to 46% for N7. Based on the in vitro toxicity and uptake data, N5-2OH was selected for in vivo biodistribution studies either in rats bearing intracerebral implants of the F98 glioma or in mice bearing either s.c. or intracerebral implants of L929 (wt) tumors. At 2.5 hours after convection-enhanced delivery, the boron values for the F98 glioma and normal brain were 16.2 ؎ 2.3 and 2.2 g/g, respectively, and the tumor to brain ratio was 8.5. Boron values at 4 hours after convection-enhanced delivery of N5-2OH to mice bearing intracerebral implants of L929 (wt) or L929 thymidine kinase-1(؊) tumors were 39.8 ؎ 10.8 and 12.4 ؎ 1.6 g/g, respectively, and the corresponding normal brain values were 4.4 and 1.6 g/g, thereby indicating that there was selective retention by the thymidine kinase-1(؉) tumors. Based on these favorable in vitro and in vivo data, neutron capture therapy studies will be initiated using N5-2OH in combination with two non-cell cycle dependent boron delivery agents, boronophenylalanine and sodium borocaptate.

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Lipophilicity and Other Parameters Affecting Brain Penetration

Cited by 52 publications

References 0 publications

Novel Tacrine‐Grafted Ugi Adducts as Multipotent Anti‐Alzheimer Drugs: A Synthetic Renewal in Tacrine–Ferulic Acid Hybrids

Novel Tacrine‐Grafted Ugi Adducts as Multipotent Anti‐Alzheimer Drugs: A Synthetic Renewal in Tacrine–Ferulic Acid Hybrids

In Silico Predictions of Blood-Brain Barrier Penetration: Considerations to “Keep in Mind”

Boron-Containing Nucleosides as Potential Delivery Agents for Neutron Capture Therapy of Brain Tumors

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