115962-35-1Relevant articles and documents
Design and Discovery of Novel Chiral Antifungal Amides with 2-(2-Oxazolinyl)aniline as a Promising Pharmacophore
Zhang, Lu,Li, Wei,Xiao, Taifeng,Song, Zehua,Csuk, René,Li, Shengkun
, p. 8957 - 8965 (2018)
Inspired by established succinate dehydrogenase inhibitors (SDHIs), our continuing efforts toward the discovery of chiral antifungal amides turned to the optimization of their polar regions with 2-(2-oxazolinyl)aniline as a known pharmacophore. Scaffold hopping and bioactivity-guided convergent synthesis enabled the identification of promising antifungal categories. Fine tuning of the substituents and chirality furnished seven amides (1s, 1t, 2d, 2h, 2j, 3k, and 2l) as antifungal candidates, with EC50 values lower than 5 mg/L. The first investigation of chiral amides of acyclic acids as SDHIs was conducted, and compound 2d was selected as a promising candidate against Botrytis cinerea, with a preventative efficacy of up to 93.9% at 50 mg/L, which is better than that of boscalid. The different binding models between compounds with different configurations were simulated for compound 2d and its diastereoisomers. The benefits of synthetic accessibility and cost-effectiveness highlight the practical potential for compound 2d as a good alternative to known SDHI fungicides.
Organocatalytic Asymmetric Cascade Reaction of 2-Hydroxyphenyl-Substituted Enones and Isocyanates to Construct 1,3-Benzoxazin-2-ones
Guo, Songsong,Liu, Xiaohua,Shen, Bin,Lin, Lili,Feng, Xiaoming
, p. 5070 - 5073 (2016)
The development of a new bisguanidinium salt as a multifunctional organocatalyst for asymmetric cascade esterification/aza-Michael reaction between 2-hydroxyphenyl-substituted enones and isocyanates is reported. A high level of enantioinduction and excell
Design, synthesis and primary activity of thiomorpholine derivatives as DPP-IV inhibitors
Han, Bei,Liu, Jing Long,Huan, Yi,Li, Peng,Wu, Qi,Lin, Zi Yun,Shen, Zhu Fang,Yin, Da Li,Huang, Hai Hong
, p. 297 - 300 (2012)
Thirteen thiomorpholine-bearing compounds were designed and synthesized as dipeptidyl peptidase IV (DPP-IV) inhibitors, with natural and non-natural l-amino acids as the starting materials. Their structures were characterized by 1H NMR, 13C NMR and HR-MS. The target compounds were screened for the DPP-IV inhibition, and the preliminary SAR result was obtained. Particularly, compounds 4c, 4d and 4f with good DPP-IV inhibition in vitro were further evaluated through a mouse oral glucose tolerance test (OGTT). The preliminary result showed the potential value for further studies on those thiomorpholine-bearing compounds as DPP-IV inhibitors.
IQCA-TASS: a nano-scaled P-selectin inhibitor capable of targeting thrombus and releasing IQCA/TARGD(S)S in vivo
Wu, Jianhui,Zhu, Haimei,Zhao, Ming,Wang, Yuji,Yang, Guodong,Wang, Yaonan,Zhao, Shurui,Gui, Lin,Zhang, Xiaoyi,Peng, Shiqi
, p. 917 - 927 (2017)
Thrombosis is a serious threat to human health worldwide. Tetrahydroisoquinoline-3-carboxylic acid (IQCA) is an antithrombotic agent, while Thr-Ala-Arg-Gly-Asp(Ser)-Ser (TASS) can target thrombus. Herein, tetrahydro-isoquinoline-3-carbonyl-Thr-Ala-Arg-Gly-Asp(Ser)-Ser (IQCA-TASS) was designed with the aim towards the discovery of a nano-delivery system for targeting thrombus. In vitro, IQCA-TASS acted on P-selectin and down-regulated P-selectin expression. The IC50 values of IQCA-TASS against the platelet aggregation induced by four aggregators were less than 0.45 nM. In vivo, IQCA-TASS targeted thrombus, released IQCA and TASS inside the thrombus, showed dose-dependent anti-thrombotic action, of which the minimal effective dose was 1 nmol kg-1, and showed anti-inflammatory action. Even with the dose up to 1 μmol kg-1, a dose of 1000 times the minimal effective dose, IQCA-TASS still induced no toxic reaction. In rat plasma, IQCA-TASS formed nanoparticles with diameters of less than 41 nm. The interactions of the nanoparticles with both resting and activated platelets were imaged. IQCA-TASS should be a safe nano-medicine capable of targeting thrombus and releasing anti-thrombotic/anti-inflammatory pharmacophores in disease sites.
Asymmetric Formal [3 + 2]-Cycloaddition of Azomethine Imines with Azlactones to Synthesize Bicyclic Pyrazolidinones
Zhang, Qian,Guo, Songsong,Yang, Jian,Yu, Kunru,Feng, Xiaoming,Lin, Lili,Liu, Xiaohua
, p. 5826 - 5829 (2017)
An efficient enantioselective formal [3 + 2]-cycloaddition of azomethine imines with azlactones has been realized by using a chiral bifunctional bisguanidinium hemisalt as the catalyst. Optically active bicyclic pyrazolidinone compounds were generated under mild reaction conditions in high yields (up to 99%) with good dr (up to 88:12) and excellent ee values (up to 99%). This simple and efficient strategy provides a method to construct biologically important chiral tetrahydropyrazolo[1,2-a]pyrazole-1,7-dione derivatives bearing vicinal aza-quaternary and tertiary carbon centers.
Design and synthesis of nanoscaled IQCA-TAVV as a delivery system capable of antiplatelet activation, targeting arterial thrombus and releasing IQCA
Wu, Jianhui,Zhu, Haimei,Yang, Guodong,He, Jianhong,Wang, Yuji,Zhao, Shurui,Zhang, Xiaoyi,Gui, Lin,Zhao, Ming,Peng, Shiqi
, p. 1139 - 1158 (2018)
Background: Arterial thrombosis has been associated with a series of pathological conditions, and the discovery of arterial thrombosis inhibitor is of clinical importance. Methods: By analyzing the pharmacophores of anti-platelet agents, thrombus targeting peptide and anti-thrombotic nano-systems 3S-1,2,3,4-tetrahydroisoquino- line-3-carbonyl-Thr-Ala- Arg-Gly-Asp(Val)-Val (IQCA-TAVV) was designed and prepared as a nano-scaled arterial thrombosis inhibitor. Results: In vitro the nanoparticles of IQCA-TAVV were able to adhere onto the surface of activated platelets, attenuate activated platelets to extend pseudopodia and inhibit activated platelets to form aggregators. In vivo IQCA-TAVV targeted arterial thrombus, dose depend- ently inhibited arterial thrombosis with a 1 nmol/kg of minimal effective dose, and the activity was ~1670 folds of that of aspirin. Conclusion: IQCA-TAVV represented the design, preparation and application of nanomedicine capable of adhering on the surface of activated platelets, attenuating platelet activation, targeting arterial thrombus and inhibiting arterial thrombosis.
Cyclic formyl and cyclic ketone compounds as well as preparation method and pharmaceutical application thereof
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Paragraph 0035; 0066-0067; 0070, (2020/08/27)
The invention discloses cyclic formyl and cyclic ketone compounds as well as a preparation method and a pharmaceutical application thereof. The compound shown in (I) has a good function of inhibitinginfection and replication of Zika viruses and dengue vir
Discovery of SHR0687, a Highly Potent and Peripheral Nervous System-Restricted KOR Agonist
Li, Xin,Wan, Hong,Dong, Ping,Wang, Bin,Zhang, Lei,Hu, Qiyue,Zhang, Ting,Feng, Jun,He, Feng,Bai, Chang,Zhang, Lianshan,Tao, Weikang
supporting information, p. 2151 - 2155 (2020/12/17)
Analgesics with no abuse liability are highly demanded in the market. KOR agonists have been proved to be strong analgesics without MOR agonist-related side effects, such as respiratory depression, tolerance, and dependence liability; however, activation
Neuroligin-2-derived peptide-covered polyamidoamine-based (PAMAM) dendrimers enhance pancreatic β-cells' proliferation and functions
Munder, Anna,Moskovitz, Yoni,Meir, Aviv,Kahremany, Shirin,Levy, Laura,Kolitz-Domb, Michal,Cohen, Guy,Shtriker, Efrat,Viskind, Olga,Lellouche, Jean-Paul,Senderowitz, Hanoch,Chessler, Steven D.,Korshin, Edward E.,Ruthstein, Sharon,Gruzman, Arie
supporting information, p. 280 - 293 (2019/03/02)
Pancreatic β-cell membranes and presynaptic areas of neurons contain analogous protein complexes that control the secretion of bioactive molecules. These complexes include the neuroligins (NLs) and their binding partners, the neurexins (NXs). It has been recently reported that both insulin secretion and the proliferation rates of β-cells increase when cells are co-cultured with full-length NL-2 clusters. The pharmacological use of full-length protein is always problematic due to its unfavorable pharmacokinetic properties. Thus, NL-2-derived short peptide was conjugated to the surface of polyamidoamine-based (PAMAM) dendrimers. This nanoscale composite improved β-cell functions in terms of the rate of proliferation, glucose-stimulated insulin secretion (GSIS), and functional maturation. This functionalized dendrimer also protected β-cells under cellular stress conditions. In addition, various novel peptidomimetic scaffolds of NL-2-derived peptide were designed, synthesized, and conjugated to the surface of PAMAM in order to increase the biostability of the conjugates. However, after being covered by peptidomimetics, PAMAM dendrimers were inactive. Thus, the original peptide-based PAMAM dendrimer is a leading compound for continued research that might provide a unique starting point for designing an innovative class of antidiabetic therapeutics that possess a unique mode of action.
Discovery of Tetrahydroisoquinoline-Containing CXCR4 Antagonists with Improved in Vitro ADMET Properties
Miller, Eric J.,Jecs, Edgars,Truax, Valarie M.,Katzman, Brooke M.,Tahirovic, Yesim A.,Wilson, Robert J.,Kuo, Katie M.,Kim, Michelle B.,Nguyen, Huy H.,Saindane, Manohar T.,Zhao, Huanyu,Wang, Tao,Sum, Chi S.,Cvijic, Mary E.,Schroeder, Gretchen M.,Wilson, Lawrence J.,Liotta, Dennis C.
, p. 946 - 979 (2018/02/17)
CXCR4 is a seven-transmembrane receptor expressed by hematopoietic stem cells and progeny, as well as by ≥48 different cancers types. CXCL12, the only chemokine ligand of CXCR4, is secreted within the tumor microenvironment, providing sanctuary for CXCR4+ tumor cells from immune surveillance and chemotherapeutic elimination by (1) stimulating prosurvival signaling and (2) recruiting CXCR4+ immunosuppressive leukocytes. Additionally, distant CXCL12-rich niches attract and support CXCR4+ metastatic growths. Accordingly, CXCR4 antagonists can potentially obstruct CXCR4-mediated prosurvival signaling, recondition the CXCR4+ leukocyte infiltrate from immunosuppressive to immunoreactive, and inhibit CXCR4+ cancer cell metastasis. Current small molecule CXCR4 antagonists suffer from poor oral bioavailability and off-target liabilities. Herein, we report a series of novel tetrahydroisoquinoline-containing CXCR4 antagonists designed to improve intestinal absorption and off-target profiles. Structure-activity relationships regarding CXCR4 potency, intestinal permeability, metabolic stability, and cytochrome P450 inhibition are presented.
