Evaluation of endo- and exo-aryl-substitutions and central scaffold modifications on diphenyl substituted alkanes as 5-lipoxygenase activating protein inhibitors
Graphical abstract
The investigation of endo and exo-aryl substitutions and the discovery of the tert-butyl group as a central scaffold on the novel class of FLAP inhibitors are reported.
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Cited by (19)
Catalytic Friedel-Crafts Reactions on Saturated Heterocycles and Small Rings for sp<sup>3</sup>-sp<sup>2</sup> Coupling of Medicinally Relevant Fragments
2019, European Journal of Organic ChemistryDrug discovery approaches targeting 5-lipoxygenase-activating protein (FLAP) for inhibition of cellular leukotriene biosynthesis
2018, European Journal of Medicinal ChemistryCitation Excerpt :In the second part of the work, Merck group focused on the modulation of 5-quinolinemethoxy-2-methyl ester 25 to improve the metabolic stability of these class of compounds, which occured as a result of the sensitivity of the central norbornane ring toward metabolic oxidation. Therefore, they systematically investigated the optimal ring/alkyl replacements of the central norbornane, and also explored the bioisosteric equivalents of ester functionality with various amide and heterocyclic substituents at 2 position of the exo-aryl ring [64]. After an extensive SAR study, they determined that mono-alkyl replacements of norbornane core such as t-butyl along with an oxadiazolone ring in place of the ester function (27) were pharmacologically beneficial resulting in improved FLAP binding (IC50 = 1.9 nM) and HWB potency (IC50 = 534 nM) as well as an acceptable PK profile (F = 27%) in the series (Fig. 7) [64].
Recent advances for FLAP inhibitors
2015, Bioorganic and Medicinal Chemistry LettersSynthesis of aromatic ketones by Suzuki-Miyaura cross-coupling of acyl chlorides with boronic acids mediated by palladium catalysts deposited over donor-functionalized silica gel
2015, Catalysis TodayCitation Excerpt :13C{1H} NMR (100.58 MHz, CDCl3, 25 °C): δ 115.7 (CN); 118.0, 128.6, 130.1, 130.2, 132.2, 133.3, 136.3 and 141.3 (aromatics); 195.0 (CO). trans-Chalcone (6m) [25]. 1H NMR (399.95 MHz, CDCl3, 25 °C): δ 7.37–7.43 (m, 3 H), 7.45–7.59 (m, 4 H) and 7.59–7.63 (m, 2 H) (aromatics); 7.80 (d, 1 H, 2JHH = 15.7 Hz, CH), 7.99–8.03 (m, 2 H, aromatics).
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