Three-dimensional rational approach to the discovery of potent substituted cyclopropyl urea soluble epoxide hydrolase inhibitors

Takai, Kentaro; Chiyo, Naoki; Nakajima, T.; Nariai, Tetsuro; Ishikawa, Chihiro; Nakatani, Shogo; Ikeno, Akihisa; Yamamoto, Seigo; Sone, Takanori

doi:10.1016/j.bmcl.2015.02.076

Cited by 15 publications

(14 citation statements)

References 34 publications

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“…To meet this goal, they synthesized and tested ~6000 compounds that ultimately yielded the non-acidic lead compound 131 as shown in Figure 55 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 49 initiated further optimization around the phenoxypiperidine region, leading to the discovery of the most potent sEH inhibitor, 144 known so far. 185 …”

Section: Bradykinin B1 Receptor Antagonist 120mentioning

confidence: 97%

The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

2016

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Recently, there has been an increasing use of the cyclopropyl ring in drug development to transition drug candidates from the preclinical to clinical stage. Important features of the cyclopropane ring are, the (1) coplanarity of the three carbon atoms, (2) relatively shorter (1.51 Å) C-C bonds, (3) enhanced π-character of C-C bonds, and (4) C-H bonds are shorter and stronger than those in alkanes. The present review will focus on the contributions that a cyclopropyl ring makes to the properties of drugs containing it. Consequently, the cyclopropyl ring addresses multiple roadblocks that can occur during drug discovery such as (a) enhancing potency, (b) reducing off-target effects,

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Section: Bradykinin B1 Receptor Antagonist 120mentioning

confidence: 97%

The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

2016

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“…Notably,c yclopropanec arboxylic acids bearing both alkyl and aryl substituents are keyb iologically active scaffolds, used as epoxide hydrolase inhibitors involved in cardiovascular disease treatment and pyrethroid insecticides. [23,24] Additionally, they may be applied as conformationally restricted peptidei sosters. [25] However,i ns pite of their importance,s ynthesis of such scaffolds with cis configuration between the carboxylic acid and an aromatic ring and trans configuration relative to the alkyl moiety remains, to the best of our knowledge, unexplored not only in enantioselective but also in ar acemic manner.…”

Section: Resultsmentioning

confidence: 99%

Enantiopure Sulfinyl Aniline as a Removable and Recyclable Chiral Auxiliary for Asymmetric C(sp³)−H Bond Activation

Jerhaoui

Chahdoura

Rose

et al. 2016

Chemistry A European J

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An original and recyclable chiral bidentate aniline-sulfoxide-based directing group has been developed. This auxiliary allows challenging stereoselective Pd-catalyzed direct functionalization of small cycloalkanes through C-aryl and C-alkyl bond formation. Although moderate diastereoselectivities are observed, both optically pure enantiomers of the highly functionalized products can be obtained separately by simple silica gel chromatography and cleavage of the chiral auxiliary. This strategy was further applied to the preparation of enantiomerically pure 1,2,3-trisubstituted cyclopropane carboxylic acid derivatives, with three stereogenic centers and bearing both alkyl and aromatic substituents. These molecular scaffolds are not yet reported in the literature. The synthetic utility of this approach is validated by the chiral auxiliary being readily cleaved and recovered posteriori to the C-H activation step, without deterioration of its optical purity. Finally, an unprecedented palladacycle intermediate generated through C-H activation of the cyclopropane moiety has been isolated and fully characterized. Initial DFT calculations shed additional light on the reactivity of this original intermediate.

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“…Furthermore, Xray crystallography research conducted by Tanaka et al revealed the binding mode of inhibitors in which the amide group creates a hydrogen bonding network with the sEH active site residues [45]. Other studies have also been conducted using fragment-based drug discovery or in silico methods and have also pointed out the importance of D335, T383, and Y466 [44,97,98]. Our studies con rm these ndings, since the largest number of interactions (both non-bonded and hydrogen bonds) were found for these amino acids.…”

Section: Discussionmentioning

confidence: 99%

Novel Potential Binding Sites for Selective Inhibitor Design of Human Soluble Epoxide Hydrolase

Bzówka

Mitusińska

Góra

2020

Preprint

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Human soluble epoxide hydrolase (hsEH) has been known to be involved in the hydrolysis of epoxyeicosatrienoic acids (EETs), which are anti-inflammatory and cardioprotective signalling molecules. Since the conversion of EETs into the corresponding diols generates non-bioactive molecules, the enzyme’s inhibition would be beneficial. hsEH quickly became the molecular target, however, the proposed inhibitors directed toward this enzyme have not undergone clinical trials, mostly due to their low solubility in water. Our goal is to indicate new regions, distinct from those already investigated, that could be considered during the development of novel and perhaps more soluble inhibitors of hsEH. To fulfil this goal, we used a combination of classical and mixed-solvent molecular dynamics (cMD and MixMD) simulations and a ligand tracking approach. Such a strategy, considers conformational changes in the interior of the enzyme, extends conformational space of binding cavities, and provides insight into different sets of potential binding modes. By analysis of the local distribution of different molecular probes (water and organic cosolvent molecules), we were able to identify potential binding sites (hot-spots), which can indicate the location of the most important functional groups for the binding of designed inhibitors. The uniqueness of the binding spots was examined by superpositioning the indicated hot-spots with a map of chemical interactions between the known inhibitors and hsEH. We analysed all available crystal structures of hsEHs with inhibitors deposited in the PDB database to gain insight into the binding modes of the known inhibitors and to find similarities and dissimilarities between them. By comparing the results obtained based on the map of chemical interactions, with the regions identified by using cMD and MixMD, we were able to identify regions that have not been targeted by ligands until now and which are promising possible binding sites for polar groups that would be beneficial for inhibitors solubility.

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Three-dimensional rational approach to the discovery of potent substituted cyclopropyl urea soluble epoxide hydrolase inhibitors

Cited by 15 publications

References 34 publications

The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

Enantiopure Sulfinyl Aniline as a Removable and Recyclable Chiral Auxiliary for Asymmetric C(sp³)−H Bond Activation

Novel Potential Binding Sites for Selective Inhibitor Design of Human Soluble Epoxide Hydrolase

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Three-dimensional rational approach to the discovery of potent substituted cyclopropyl urea soluble epoxide hydrolase inhibitors

Cited by 15 publications

References 34 publications

The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

Enantiopure Sulfinyl Aniline as a Removable and Recyclable Chiral Auxiliary for Asymmetric C(sp3)−H Bond Activation

Novel Potential Binding Sites for Selective Inhibitor Design of Human Soluble Epoxide Hydrolase

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Enantiopure Sulfinyl Aniline as a Removable and Recyclable Chiral Auxiliary for Asymmetric C(sp³)−H Bond Activation