Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3

Nakajima, Yutaka; Inoue, Takayuki; Nakai, Kengo; Mukoyoshi, Koichiro; Hamaguchi, Hisao; Hatanaka, Keiko; Sasaki, Hiroshi; Takahashi, Fumie; Usuda, Hiroyuki; Moritomo, Ayako; Higashi, Yasuyuki; Inami, Masamichi; Shirakami, Shohei

doi:10.1016/j.bmc.2015.05.034

Cited by 21 publications

(18 citation statements)

References 39 publications

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“…5F4IPP has a pyridine ring fused with pyrrole ring (Supplementary Fig. S2B), and its pyridine ring has a nitrogen atom at the para position instead of the methine group (=CH−) in benzene ring which selectively differentiates pyrroles and indoles 50,51 . 5F4IPP also has one additional electronegative nitrogen atom that can actively participate in hydrogen bonding and a highly electronegative fluorine (Fig.…”

Section: Discussionmentioning

confidence: 99%

Nematicidal and insecticidal activities of halogenated indoles

Rajasekharan

Lee

Ravichandran

et al. 2019

Sci Rep

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Parasite death via ion channel activations is the hallmark of anthelmintic and antiparasitic drugs. Glutamate gated chloride channel (GluCl) is a prominent targets for drug selection and design in parasitology. We report several iodine-fluorine based lead activators of GluCl by computational studies and structure-activity relationship analysis. 5-Fluoro-4-iodo-1H-pyrrolo [2, 3-b] pyridine and 5-iodoindole were bioactive hits that displayed in vitro anthelmintic and insecticidal activities against Bursaphelenchus xylophilus, Meloidogyne incognita, and Tenebrio molitor. Two important findings stood out: (i) 5F4IPP induced parasite death, and interacted proficiently with Gln219 amino acid of pentameric GluCl in docking analysis, and (ii) 5-iodoindole appeared to act by forming giant vacuoles in nematodes, which led to a form of non-apoptotic death known as methuosis. The study suggests halogenated-indoles and 1H-pyrrolo [2, 3-b] pyridine derivatives be regarded potential biocides for plant-parasitic nematodes and insects, and warrants further research on the mode of actions, and field investigations.

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Section: Discussionmentioning

confidence: 99%

Nematicidal and insecticidal activities of halogenated indoles

Rajasekharan

Lee

Ravichandran

et al. 2019

Sci Rep

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“…Column chromatography was performed using Kieselgel Merck 60 (230−400 mesh) as the stationary phase. 1 H, 19 F, and 13 C NMR spectra were recorded at 500 or 400 MHz, 470 or 376 MHz, and 126 MHz or 101 MHz, respectively. Chemical shifts are reported in ppm downfield from tetramethylsilane as an internal standard.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…Over the past decades, fluorine has become the most influential halogen in drug discovery, resulting in about one-third of currently marketed pharmaceuticals being represented by fluorinated derivatives. − The ability of fluorine to modulate physicochemical and conformational properties is commonly used to adjust the lead potency, metabolic pathways, membrane permeability, etc. − Apart from that, introduction of fluorine atoms in proximity to a basic amine center was found to be beneficial for reduction of hERG inhibition , and reduction of P -glycoprotein efflux …”

Section: Introductionmentioning

confidence: 99%

“…1−5 The ability of fluorine to modulate physicochemical and conformational properties is commonly used to adjust the lead potency, metabolic pathways, membrane permeability, etc. 6−11 Apart from that, introduction of fluorine atoms in proximity to a basic amine center was found to be beneficial for reduction of hERG inhibition 12,13 and reduction of P-glycoprotein efflux. 14 Among the known variety of fluorinated organic motifs, the gem-difluoromethylene unit is of special interest for medicinal chemistry.…”

Section: ■ Introductionmentioning

confidence: 99%

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Last of the gem-Difluorocycloalkanes: Synthesis and Characterization of 2,2-Difluorocyclobutyl-Substituted Building Blocks

et al. 2019

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An efficient approach to synthesis of previously unavailable 2-substituted difluorocyclobutane building blocks was developed and applied on a multigram scale. The key step of the synthetic sequence included deoxofluorination of O-protected 2-(hydroxylmethyl)cyclobutanone. Dissociation constants (pK a) and log P values for 2,2-difluorocyclobutaneamine and 2,2-difluorocyclobutanecarboxylic acid or their derivatives were measured and compared with the values obtained for the corresponding 3,3-difluorocyclobutane derivatives and nonfluorinated counterparts. Three-dimensional structures of 2,2- and 3,3-difluorocyclobutanamines were compared using exit vector plot analysis of X-ray crystallographic data.

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“…35 Mice and humans with defected JAK3 gene show immune deficiency, inhibiting the function of T lymphocytes. 36,37 And JAK3 gene mutation may cause natural killer-cell lymphoma 38,39 and T-lymphocyte prolymphocytic leukemia. 40,41 Thus, the restricted expression and function of JAK3 make it a potential therapeutic target.…”

Section: Discussionmentioning

confidence: 99%

A benzoxazole derivative PO‐296 inhibits T lymphocyte proliferation by the JAK3/STAT5 signal pathway

Luo

Zhou

Wang

et al. 2018

J of Cellular Biochemistry

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Immunosuppressants have shown striking achievements in treating autoimmune diseases in recent years. It is urgent to develop more immunosuppressants to provide more options for patients. oxazol-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol] was identified as a novel benzoxazole derivative. We observed that it exhibits an obvious immunosuppressive activity to T lymphocytes. PO-296 significantly inhibited the proliferation of activated human T lymphocyte without cytotoxicity. Moreover, PO-296 did not affect the expression of cluster of differentiation (CD)-25 or CD69 but induced T lymphocyte cycle arrest in the G0/ G1 phase. Furthermore, PO-296 inhibited interleukin (IL)-6, IL-17, and interferon gamma expression but had no effect on IL-2, IL-4, or IL-10. Yet, importantly, PO-296 inhibited the phosphorylation of signal transducer and activator of transcription 5 (STAT5), increased the phosphorylation of p70S6K, but did not affect the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mitogen-activated protein kinase pathway. In conclusion, these findings indicate that PO-296 inhibits human activated T-lymphocyte proliferation by affecting the janus kinase 3 (JAK3)/STAT5 pathway. PO-296 possesses a potential lead compound for the design and development of new immunosuppressants for the treatment of autoimmune diseases.

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Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3

Cited by 21 publications

References 39 publications

Nematicidal and insecticidal activities of halogenated indoles

Nematicidal and insecticidal activities of halogenated indoles

Last of the gem-Difluorocycloalkanes: Synthesis and Characterization of 2,2-Difluorocyclobutyl-Substituted Building Blocks

A benzoxazole derivative PO‐296 inhibits T lymphocyte proliferation by the JAK3/STAT5 signal pathway

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