CNS Physicochemical Property Space Shaped by a Diverse Set of Molecules with Experimentally Determined Exposure in the Mouse Brain

Rankovic, Zoran

doi:10.1021/acs.jmedchem.6b01469

Cited by 83 publications

(98 citation statements)

References 49 publications

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“…We determined the CNS desirability score for 73 of the GBM drug candidates reported in Table 1 , using the CNS MPO.v2 algorithm ( Fig. 9A ) ( Rankovic, 2017 ). The CNS MPO.v2 desirability score weighs five important CNS physicochemical properties, molecular mass, lipophilicity (ClogP), number of hydrogen bond donors, topical polar surface area, and p K a (of the most basic center), from 0 to 1.…”

Section: Blood-brain Barriermentioning

confidence: 99%

Current Challenges and Opportunities in Treating Glioblastoma

et al. 2018

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Glioblastoma multiforme (GBM), the most common and aggressive primary brain tumor, has a high mortality rate despite extensive efforts to develop new treatments. GBM exhibits both intra- and intertumor heterogeneity, lending to resistance and eventual tumor recurrence. Large-scale genomic and proteomic analysis of GBM tumors has uncovered potential drug targets. Effective and “druggable” targets must be validated to embark on a robust medicinal chemistry campaign culminating in the discovery of clinical candidates. Here, we review recent developments in GBM drug discovery and delivery. To identify GBM drug targets, we performed extensive bioinformatics analysis using data from The Cancer Genome Atlas project. We discovered 20 genes, BOC, CLEC4GP1, ELOVL6, EREG, ESR2, FDCSP, FURIN, FUT8-AS1, GZMB, IRX3, LITAF, NDEL1, NKX3-1, PODNL1, PTPRN, QSOX1, SEMA4F, TH, VEGFC, and C20orf166AS1 that are overexpressed in a subpopulation of GBM patients and correlate with poor survival outcomes. Importantly, nine of these genes exhibit higher expression in GBM versus low-grade glioma and may be involved in disease progression. In this review, we discuss these proteins in the context of GBM disease progression. We also conducted computational multi-parameter optimization to assess the blood-brain barrier (BBB) permeability of small molecules in clinical trials for GBM treatment. Drug delivery in the context of GBM is particularly challenging because the BBB hinders small molecule transport. Therefore, we discuss novel drug delivery methods, including nanoparticles and prodrugs. Given the aggressive nature of GBM and the complexity of targeting the central nervous system, effective treatment options are a major unmet medical need. Identification and validation of biomarkers and drug targets associated with GBM disease progression present an exciting opportunity to improve treatment of this devastating disease.

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Section: Blood-brain Barriermentioning

confidence: 99%

Current Challenges and Opportunities in Treating Glioblastoma

et al. 2018

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“…22,27 In relation to CNS drug discovery, large molecular weight (> 470 Da), large topological polar surface area (tPSA > 90 Å), numerous hydrogen bond donors (HBD > 2), and the presence of carboxylic acid groups generally impede blood-brain barrier (BBB) penetration. 47,48 The CNS permeability has been experimentally tested on a few Keap1 inhibitors (3 and 13) but with discouraging results, 30,41 and based on their low CNS multiparameter optimization (CNS MPO) scores, 47,48 the other reported inhibitors would not be expected to pass the BBB either. 10 One strategy for addressing the issues listed above is to optimize known Keap1 inhibitors for cell and CNS activity.…”

Section: Introductionmentioning

confidence: 99%

A Comparative Assessment Study of Known Small-Molecule Keap1−Nrf2 Protein–Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity

et al. 2019

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Inhibiting the protein-protein interaction (PPI) between the transcription factor Nrf2 and its repressor protein Keap1 has emerged as a promising strategy to target oxidative stress in diseases, including CNS disorders. Numerous non-covalent small-molecule Keap1-Nrf2 PPI inhibitors have been reported to date, but many feature suboptimal physicochemical properties for permeating the blood-brain barrier, while others contain problematic structural moieties. Here, we present the first side-by-side assessment of all reported Keap1-Nrf2 PPI inhibitor classes using fluorescence polarization (FP), thermal shift assay (TSA), and surface plasmon resonance (SPR)-and further evaluate the compounds in an NQO1 induction cell assay and in counter tests for non-boronate ester building block 41 as the crucial carbon skeleton-building step. Synthesis of the enol triflate using the one-step NaHMDS-mediated enolization/PhNTf2-induced trapping procedure reported in the patent application 39 was not efficient in our hands, giving low yield (43% vs. 88% reported in literature 39) and significant byproduct formation. We found that using a freshly-made LiHMDS as an alternative base gave a cleaner reaction and excellent yield (quantitative). The converging SM reaction step between 38 and 41 gave several wellknown by-products, including the boronic acid, aryl boronate homo-coupling product and protodeboronation product, but could still afford the desired cross-coupling product 42 in good yield (69% vs. 33% reported in literature 39). Catalytic hydrogenation to deprotect the carboxylic acid and reduce the alkene double bond diastereoselectively furnished only the cis-cyclohexane 43 in accordance with literature; 39 this was revealed by nuclear Overhauser effect (NOE) NMR (Supporting Information Figure S1). This facial selectivity can be explained by a steric directing effect of the carboxybenzyl group. The cyclohexane carboxylic acid of 43 was finally coupled with 2-butylpyrrolidine and the pyrazole carboxylic acid deprotected to give 10 as a mixture of four stereoisomers. Attempted separation of the two diastereoisomers by preparative HPLC was unsuccessful. In the patent application, purification by HPLC is reported to give two different fractions, each containing all four stereoisomers in slightly different proportions, of which one was directly tested as a mixture. 39 Having this literature result as a reference point, we did not proceed with further purification of 10.

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“…This emphasizes the importance of ionization and lipophilicity adjusted for ionization [13,23,28,29]. Recently Z. Ranković further refined the CNS desirability criteria in CNS MPOv.2 [30].…”

Section: Lipophilicity and Oral Absorptionmentioning

confidence: 99%

Leveraging chromatography based physicochemical properties for efficient drug design

Goetz

Shalaeva²

2018

ADMET DMPK

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<p class="ADMETabstracttext">Applications of chromatography derived lipophilicity, polarity, and 3D concepts such as conformational states, exposed polarity and intramolecular hydrogen bonds (IMHB), are discussed along with recently developed methods for incorporating these concepts into drug design strategies. In addition, the drug design process is described with examples and practices used at Pfizer, as well as experimental and computed parameters used for parallel optimization of properties leading to drug candidate nominations.</p>

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CNS Physicochemical Property Space Shaped by a Diverse Set of Molecules with Experimentally Determined Exposure in the Mouse Brain

Cited by 83 publications

References 49 publications

Current Challenges and Opportunities in Treating Glioblastoma

Current Challenges and Opportunities in Treating Glioblastoma

A Comparative Assessment Study of Known Small-Molecule Keap1−Nrf2 Protein–Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity

Leveraging chromatography based physicochemical properties for efficient drug design

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