28466-26-4Relevant articles and documents
Indazole, Pyrazole, and Oxazole Derivatives Targeting Nitric Oxide Synthases and Carbonic Anhydrases
Maccallini, Cristina,Di Matteo, Mauro,Vullo, Daniela,Ammazzalorso, Alessandra,Carradori, Simone,De Filippis, Barbara,Fantacuzzi, Marialuigia,Giampietro, Letizia,Pandolfi, Assunta,Supuran, Claudiu T.,Amoroso, Rosa
, p. 1695 - 1699 (2016)
Nitric oxide (NO) is an essential endogenous mediator with a physiological role in the central nervous system as neurotransmitter and neuromodulator. A growing number of studies have demonstrated that abnormal nitrergic signaling is a crucial event in the development of neurodegeneration. In particular, the uncontrolled production of NO by neuronal nitric oxide synthase (nNOS) is observed in several neurodegenerative diseases. Moreover, it is well recognized that specific isoforms of human carbonic anhydrase (hCA) physiologically modulate crucial pathways of signal processing and that low expression of CA affects cognition, leading to mental retardation, Alzheimer′s disease, and aging-related cognitive impairments. In light of this, dual agents that are able to target both NOS (inhibition) and CA (activation) could be useful drug candidates for the treatment of Alzheimer′s disease, aging, and other neurodegenerative diseases. In the present work, we show the design, synthesis, and in vitro biological evaluation of new nitrogen-based heterocyclic compounds. Among the tested molecules, 2-amino-3-(4-hydroxyphenyl)-N-(1H-indazol-5-yl)propanamide hydrochloride (10 b) was revealed to be a potent dual agent, able to act as a selective nNOS inhibitor and activator of the hCA I isoform.
Discovery of Novel Pyrrolo[2,3-d]pyrimidine-based Derivatives as Potent JAK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors
Liang, Xuewu,Tang, Shuai,Liu, Xuyi,Liu, Yingluo,Xu, Qifu,Wang, Xiaomin,Saidahmatov, Abdusaid,Li, Chunpu,Wang, Jiang,Zhou, Yu,Zhang, Yingjie,Geng, Meiyu,Huang, Min,Liu, Hong
, p. 1243 - 1264 (2021/03/01)
It remains a big challenge to develop HDAC inhibitors effective for solid tumors. Previous studies have suggested that the feedback activation of JAK-STAT3 pathway represents a key mechanism leading to resistance to HDAC inhibitors in breast cancer, suggesting the therapeutic promise of JAK/HDAC dual inhibitors. In this work, we discovered a series of pyrrolo[2,3-d]pyrimidine-based derivatives as potent JAK and HDAC dual inhibitors. Especially, compounds 15d and 15h potently inhibited JAK1/2/3 and HDAC1/6 and displayed antiproliferative and proapoptotic activities in triple-negative breast cancer cell lines. Besides, compounds 15d and 15h also diminished the activation of LIFR-JAK-STAT signaling triggered by tumor-associated fibroblasts, which suggests that these compounds could potentially overcome the drug resistance caused by the tumor microenvironment. More importantly, compound 15d effectively inhibited the tumor growth in MDA-MB-231 xenograft tumor model. Overall, this work provides valuable leads and novel antitumor mechanisms for the treatment of the SAHA-resistant triple-negative breast cancers.
INHIBITORS OF NECROPTOSIS
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Page/Page column 44, (2021/09/04)
This invention relates to compounds of Formula (I) and salts, solvates, prodrugs, tautomers, N-oxides, stereoisomers, polymorphs and physiologically functional derivatives thereof. Also disclosed are methods of use of Formula (I), including in the inhibition of necroptosis and treatment of associated diseases, conditions and/or disorders.
Discovery of imidazopyrrolopyridines derivatives as novel and selective inhibitors of JAK2
Xu, Pengfei,Shen, Pei,Wang, Hai,Qin, Lian,Ren, Jie,Sun, Qiushuang,Ge, Raoling,Bian, Jinlei,Zhong, Yi,Li, Zhiyu,Wang, JuBo,Qiu, Zhixia
, (2021/04/09)
Herein, we describe the design, synthesis, and structure?activity relationships of a series of imidazopyrrolopyridines derivatives that selectively inhibit Janus kinase 2 (JAK2). These screening cascades revealed that 6k was a preferred compound, with IC50 values of 10 nM for JAK2. Moreover, 6k was a selective JAK2 inhibitor with 19-fold, >30-fold and >30-fold selectivity over JAK1, JAK3 and TYK2 respectively. In cytokine-stimulated cell-based assays, 6k exhibited a higher JAK2 selectivity over JAK1 isoforms. Indeed, at a dose of 20 mg/kg compound 6k, pSTAT3 and pSTAT5 expression was reduced to levels comparable to those of control animals untreated with GM-CSF. Additionally, 6k showed a relatively good bioavailability (F = 38%), a suitable half-life time (T1/2 = 1.9 h), a satisfactory metabolic stability, suggesting that 6k might be a promising inhibitor of JAK2 for further development research for the treatment of MPNs.
Thiophene-Pyrazolourea Derivatives as Potent, Orally Bioavailable, and Isoform-Selective JNK3 Inhibitors
Feng, Yangbo,Park, Hajeung,Bauer, Luke,Ryu, Jae Cheon,Yoon, Sung Ok
supporting information, p. 24 - 29 (2021/01/12)
Potent JNK3 isoform selective inhibitors were developed from a thiophenyl-pyrazolourea scaffold. Through structure activity relationship (SAR) studies utilizing enzymatic and cell-based assays, and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies, potent and highly selective JNK3 inhibitors with oral bioavailability and brain penetrant capability were developed. Inhibitor 17 was a potent and isoform selective JNK3 inhibitor (IC50 = 35 nM), had significant inhibition to only JNK3 in a panel profiling of 374 wild-type kinases, had high potency in functional cell-based assays, had high stability in human liver microsome (t1/2 = 66 min) and a clean CYP-450 inhibition profile, and was orally bioavailable and brain penetrant. Moreover, cocrystal structures of compounds 17 and 27 in human JNK3 were solved at 1.84 ?, which showed that these JNK3 isoform selective inhibitors bound to the ATP pocket, had interactions in both hydrophobic pocket-I and hydrophobic pocket-II.
Design and synthesis of anti-tumor compounds containing ferulic acid-pyrazole skeleton
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Paragraph 0024-0025; 0029; 0031-0032; 0035, (2021/04/28)
The invention discloses design and a preparation method of an anti-tumor compound containing a ferulic acid-pyrazole skeleton. The structure of the anti-tumor compound is shown as a formula in the specification.
Discovery of Novel Janus Kinase (JAK) and Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Hematological Malignancies
Liang, Xuewu,Zang, Jie,Li, Xiaoyang,Tang, Shuai,Huang, Min,Geng, Meiyu,Chou, C. James,Li, Chunpu,Cao, Yichun,Xu, Wenfang,Liu, Hong,Zhang, Yingjie
, p. 3898 - 3923 (2019/04/25)
Concurrent inhibition of Janus kinase (JAK) and histone deacetylase (HDAC) could potentially improve the efficacy of the HDAC inhibitors in the treatment of cancers and resolve the problem of HDAC inhibitor resistance in some tumors. Here, a novel series
Aromatic amine compound synthesis method
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Paragraph 0259-0261, (2019/01/23)
The invention discloses an aromatic amine compound synthesis method which is characterized in that the method is implemented according to any of two methods. The first method includes the steps: mixing an alkyl aromatic compound with a general formula (I) and a nitrogen-containing compound with a general formula (II); performing reaction on mixture under an oxidizing agent and an organic solvent to obtain an aromatic amine compound with a general formula (III). The second method includes the steps: mixing an aromatic alcohol derivative with a general formula (I') and the nitrogen-containing compound with the general formula (II); performing reaction on mixture under an acid additive and an organic solvent to prepare the aromatic amine compound with the general formula (III). According to the method, a lot of alkyl aromatic compounds or aromatic alcohol derivatives firstly serve as raw materials, and the raw materials are reacted to generate the aromatic amine compound without the action of metal catalysis. Compared with a traditional synthesis method, the synthesis method has the advantages that the method is high in yield and simple in condition, waste discharging amount is less,metal participation is omitted, a reaction device is simple, industrial production is easily achieved and the like. The method has a wide application prospect.
JAK (Janus kinase) and HDAC (histone deacetylase) double-target-spot inhibitor with 4-aminopyrazole structure, and preparation method and application thereof
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Paragraph 0105; 0206-0208, (2018/12/14)
The invention relates to a JAK (Janus kinase) and HDAC (histone deacetylase) double-target-spot inhibitor with a 4-aminopyrazole structure, a preparation method thereof and application of the compoundto preparation of drugs for preventing or treating bloo
ARYLAMIDE DERIVATIVES HAVING MULTIMODAL ACTIVITY AGAINST PAIN
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Page/Page column 297, (2017/11/10)
The present invention relates to arylamide derivatives having dual pharmacological activity towards both the α2δ subunit, in particular the α2δ-1 subunit,of the voltage-gated calcium channel and the μ-opioid receptor, to processes of preparation of such c
