Structure–activity relationships and key structural feature of pyridyloxybenzene-acylsulfonamides as new, potent, and selective peroxisome proliferator-activated receptor (PPAR) γ Agonists

Rikimaru, Kentaro; Wakabayashi, Tomonari; Abe, Hidenori; Tawaraishi, Taisuke; H, Ito; Yonemori, Jinichi; Hirose, Hideki; Murase, Kouhei; Matsuo, Taisuke; Matsumoto, Mitsuharu; Nomura, Chisako; Tsuge, Hiroko; Arimura, Naoto; Kawakami, Kazutoshi; Sakamoto, Junichi; Funami, Miyuki; Mol, Clifford D.; Snell, G.; Bragstad, Kenneth A.; Sang, Bi‐Ching; Dougan, D.R.; Tanaka, Toshimasa; Katayama, Nozomi; Horiguchi, Yoshiaki; Momose, Yū

doi:10.1016/j.bmc.2012.03.036

Cited by 12 publications

(11 citation statements)

References 32 publications

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“…Use of an unsubstituted glycine linker (30, R 1 = R 2 = H) resulted in weak inhibitory activity (IC 50 = 3.6 μM). Alkyl substitution significantly increased potency compared to 30; linkers with (S)-methyl, dimethyl, (R)-ethyl, and (S)-isopropyl substitution (31,41,35,33) displayed potent c-Met inhibition with IC 50 of 63 nM, 39 nM, 22 nM and 72 nM, respectively. Compounds 42-45 with cycloalkyl or benzyl substitution also showed potent inhibition (IC 50 = 22-130 nM).…”

Section: Resultsmentioning

confidence: 98%

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Design and synthesis of 3,3′-biscoumarin-based c-Met inhibitors

Liu

et al. 2014

Org. Biomol. Chem.

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A library of biscoumarin-based c-Met inhibitors was synthesized, based on optimization of 3,3'-biscoumarin hit 3, which was identified as a non-ATP competitive inhibitor of c-Met from a diverse library of coumarin derivatives. Among these compounds, 38 and 40 not only showed potent enzyme activities with IC50 values of 107 nM and 30 nM, respectively, but also inhibited c-Met phosphorylation in BaF3/TPR-Met and EBC-1 cells.

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Section: Resultsmentioning

confidence: 98%

“…Compounds 19 (ref. 25) and 56a-b (ref 33,34). were prepared utilizing the same synthetic route as compound 9d starting from different salicylaldehydes.2-Hydroxy-3,4-bis(methoxymethoxy)benzaldehyde(19).…”

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confidence: 99%

Design and synthesis of 3,3′-biscoumarin-based c-Met inhibitors

Liu

et al. 2014

Org. Biomol. Chem.

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“…It was found that when treprostinil ethyl ester 7 was treated with the Dudley reagent (2-benzyloxy-1-methylpridinium triflate) 39 Coupling was achieved using two different reagents reported in the literature. 40 To avoid the aforementioned limitations, we found that it was possible to prepare treprostinil N-acyl methylsulfonamide 5 in 20% isolated yield after purification by the alkylation of the triol precursor 12 with the bromo-sulfonamide adduct 14 using excess NaH (Scheme 3B). 43 Excess NaH was required due to the acidic proton in the bromo-sulfonamide 14 to give the desired treprostinil N-acyl methylsulfonamide 5.…”

Section: Resultsmentioning

confidence: 99%

Synthetic routes to treprostinil N-acyl methylsulfonamide

Picken

Laing

Shen

et al. 2020

Tetrahedron Letters

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The synthesis of the prodrug candidate, treprostinil N-acyl methylsulfonamide 5 was accomplished from treprostinil 2 utilising protecting group strategies. A more direct synthesis for the prodrug was also achieved using a treprostinil triol precursor 12 and bromoacetyl acylmethylsulfonamide 14. The overall yield of treprostinil N-acyl sulfonamide 5 directly from the triol precursor 12 is similar to the protecting group strategies because deprotonation of the acidic proton in the bromoacetyl acylmethylsulfonamide 14 reduces electrophilicity. However, the more direct route using the treprostinil triol precursor holds greater promise as a strategy to prepare a wide range of treprostinil prodrug candidates. Treprostinil N-acyl methylsulfonamide prodrug 5 exhibited a 30-fold decrease in the potency at the human prostacyclin (IP) receptor compared to treprostinil 2 in an in vitro cyclic AMP assay.

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“…A novel class of pyridyloxybenzene-acylsulfonamides as non-thiazolidinedione (TZD), non-carboxylic-acid-based selective PPAR agonists has been reported by Rikimaru et al [18]. The aim of present communication is to establish the quantitative relationships between the reported activities and molecular descriptors unfolding the substitutional changes in titled compounds.…”

Section: Introductionmentioning

confidence: 88%

“…The reported thirty four pyridyloxybenzene-acylsulfonamidesare considered as the data set for this study [18]. These derivatives were evaluated for their transactivation activity against human PPAR stably expressed in Chinese hamster ovary (CHO) -K1 cells.…”

Section: Biological Actions and Theoretical Molecular Descriptorsmentioning

confidence: 99%

CP-MLR derived QSAR rationales for the PPARy agonistic activity of the pyridyloxybenzene-acylsulfonamide derivatives

Parihar

Afsar

Kishore

2020

GSC Biol. and Pharm. Sci.

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QSAR rationales have been obtained for the PPAR transactivation activity of pyridyloxybenzene-acylsulfonamides in terms of 0D-to 2D-Dragon descriptors. The descriptors identified in CP-MLR analysis have highlighted the role of atomic mass, van der Waals volumes and polarizability through weighted 2D autocorrelations (GATS1v and GATS1p), modified Burden eigenvalue (BEHm4) and molecular weight (MW). Sum of topological distances between O and S atoms (descriptor T(O..S)), and N and Cl atoms (descriptor T(N..Cl)), average connectivity index chi-1(X1A) and Quadratic index (Qindex) have also shown dominance to optimize the PPARγ transactivation. Descriptors RBN and RBF suggested presence of rotatable bonds in a molecular structure for better PPAR activity. Applicability domain analysis revealed that the suggested model matches the high quality parameters with good fitting power and the capability of assessing external data and all of the compounds was within the applicability domain of the proposed model and were evaluated correctly.

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Structure–activity relationships and key structural feature of pyridyloxybenzene-acylsulfonamides as new, potent, and selective peroxisome proliferator-activated receptor (PPAR) γ Agonists

Cited by 12 publications

References 32 publications

Design and synthesis of 3,3′-biscoumarin-based c-Met inhibitors

Design and synthesis of 3,3′-biscoumarin-based c-Met inhibitors

Synthetic routes to treprostinil N-acyl methylsulfonamide

CP-MLR derived QSAR rationales for the PPARy agonistic activity of the pyridyloxybenzene-acylsulfonamide derivatives

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