Synthesis and evaluation of isoxazole derivatives as lysophosphatidic acid (LPA) antagonists

Yamamoto, Takashi; Fujita, Köichi; Asari, Sayaka; Chiba, Akira; Kataba, Yuka; Ohsumi, Koji; Ohmuta, Naoko; Iida, Yuko; Ijichi, Chiori; Fukuchi, Naoyuki; Shoji, Masataka

doi:10.1016/j.bmcl.2007.04.024

Cited by 32 publications

(25 citation statements)

References 28 publications

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“…For the synthesis and biological activity of soxazoles, see; Silva et al (2002); Changtam et al (2010); Patel et al (2010); Barceló et al (2007); Yamamoto et al (2007); Mao et al (2010). For their structure-activity relationships, see: Andrzejak et al (2011); Becht et al (2006); Veronese et al (1997).…”

Section: Related Literaturementioning

confidence: 98%

Ethyl 5-(4-aminophenyl)isoxazole-3-carboxylate

Zhao

Zhou

et al. 2012

Acta Cryst E

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The asymmetric unit of the title compound, C12H12N2O3, contains two molecules in which the benzene and isoxazole rings are almost coplanar, the dihedral angles between their mean planes being 1.76 (9) and 5.85 (8)°. The two molecules interact with each other via N—H⋯N and N—H⋯O hydrogen bonds, which link the molecules into layers parallel to the ac plane. The layers stack in a parallel mode with an interlayer distance of 3.36 (7) Å.

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Section: Related Literaturementioning

confidence: 98%

Ethyl 5-(4-aminophenyl)isoxazole-3-carboxylate

Zhao

Zhou

et al. 2012

Acta Cryst E

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“…30,31 By taking bioisostere approaches, we discovered pyrazole and triazole-derived LPA1 selective and LPA1/3 dual antagonists. Compound 2 demonstrated the highest LPA1 selectivity and attenuated LPA-induced NHLF proliferation and contraction with high potency.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Discovery of Highly Selective and Orally Active Lysophosphatidic Acid Receptor-1 Antagonists with Potent Activity on Human Lung Fibroblasts

Qian¹,

Hamilton²,

Sidduri³

et al. 2012

J. Med. Chem.

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Lysophosphatidic acid is a class of bioactive phospholipid that mediates most of its biological effects through LPA receptors, of which six isoforms have been identified. The recent results from LPA1 knockout mice suggested that blocking LPA1 signaling could provide a potential novel approach for the treatment of idiopathic pulmonary fibrosis. Here, we report the design and synthesis of pyrazole- and triazole-derived carbamates as LPA1-selective and LPA1/3 dual antagonists. In particular, compound 2, the most selective LPA1 antagonist reported, inhibited proliferation and contraction of normal human lung fibroblasts (NHLF) following LPA stimulation. Oral dosing of compound 2 to mice resulted in a dose-dependent reduction of plasma histamine levels in a murine LPA challenge model. Furthermore, we applied our novel antagonists as chemistry probes and investigated the contribution of LPA1/2/3 in mediating the pro-fibrotic responses. Our results suggest LPA1 as the major receptor subtype mediating LPA-induced proliferation and contraction of NHLF.

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“…Intermediates from the above two steps were used directly without any purification. Compounds 15a, 16a and 17a were prepared according to the reported methods [23][24][25]. By reference to Kamal's report, compounds 18a~30a were synthesized from the corresponding substituted acetophenones [26].…”

Section: Chemistrymentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of Stilbene Derivatives as Novel Inhibitors of Protein Tyrosine Phosphatase 1B

Dai

et al. 2016

Molecules

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Abstract:By imitating the scaffold of lithocholic acid (LCA), a natural steroidal compound displaying Protein Tyrosine Phosphatase 1B (PTP1B) inhibitory activity, a series of stilbene derivatives containing phenyl-substituted isoxazoles were designed and synthesized. The structures of the title compounds were confirmed by 1 H-NMR, 13 C-NMR and HRMS. Activities of the title compounds were evaluated on PTP1B and the homologous enzyme TCPTP by using a colorimetric assay. Most of the target compounds had good activities against PTP1B. Among them, compound 29 (IC 50 = 0.91 ± 0.33 µM), characterized by a 5-(2,3-dichlorophenyl) isoxazole moiety, exhibited an activity about 14-fold higher than the lead compound LCA and a 4.2-fold selectivity over TCPTP. Compound 29 was identified as a competitive inhibitor of PTP1B with a K i value of 0.78 µM in enzyme kinetic studies.

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Synthesis and evaluation of isoxazole derivatives as lysophosphatidic acid (LPA) antagonists

Cited by 32 publications

References 28 publications

Ethyl 5-(4-aminophenyl)isoxazole-3-carboxylate

Ethyl 5-(4-aminophenyl)isoxazole-3-carboxylate

Discovery of Highly Selective and Orally Active Lysophosphatidic Acid Receptor-1 Antagonists with Potent Activity on Human Lung Fibroblasts

Design, Synthesis and Biological Evaluation of Stilbene Derivatives as Novel Inhibitors of Protein Tyrosine Phosphatase 1B

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