Category: 89793-12-4

Wang, Manjiong; Tang, Tongke; Li, Ruoxi; Huang, Zhenghui; Ling, Dazheng; Zheng, Lulu; Ding, Yan; Liu, Taiping; Xu, Wenyue; Zhu, Feng; Min, Hui; Boonhok, Rachasak; Mao, Fei; Zhu, Jin; Li, Xiaokang; Jiang, Lubin; Li, Jian published the artcile< Drug Repurposing of Quisinostat to Discover Novel Plasmodium falciparum HDAC1 Inhibitors with Enhanced Triple-Stage Antimalarial Activity and Improved Safety>, HPLC of Formula: 89793-12-4, the main research area is quisinostat derivative preparation resistant malaria drug repurposing.

Our previous work found that the clin. histone deacetylase (HDAC) inhibitor quisinostat exhibited a significant antimalarial effect but with severe toxicity. In this work, 35 novel derivatives were designed and synthesized based on quisinostat as the lead compound, and their in vitro antimalarial activities and cytotoxicities were systematically evaluated. Among them, JX35 showed potent inhibition against both wild-type and multidrug-resistant parasite strains and displayed a significant in vivo killing effect against all life cycles of parasites, including the blood stage, liver stage, and gametocyte stage, indicating its potential for the simultaneous treatment, chemoprevention, and blockage of malaria transmission. Compared with quisinostat, JX35 exhibited stronger antimalarial efficacy, more adequate safety, and good pharmacokinetic properties. Addnl., mechanistic studies via mol. docking studies, induced PfHDAC1/2 knockdown assays, and PfHDAC1 enzyme inhibition assays jointly indicated that the antimalarial target of JX35 was PfHDAC1. In summary, we discovered the promising candidate PfHDAC1 inhibitor JX35, which showed stronger triple-stage antimalarial effects and lower toxicity than quisinostat.

Journal of Medicinal Chemistry published new progress about Antimalarials. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, HPLC of Formula: 89793-12-4.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Rabal, Obdulia; Sanchez-Arias, Juan A.; Cuadrado-Tejedor, Mar; de Miguel, Irene; Perez-Gonzalez, Marta; Garcia-Barroso, Carolina; Ugarte, Ana; Estella-Hermoso de Mendoza, Ander; Saez, Elena; Espelosin, Maria; Ursua, Susana; Tan, Haizhong; Wu, Wei; Xu, Musheng; Pineda-Lucena, Antonio; Garcia-Osta, Ana; Oyarzabal, Julen published the artcile< Multitarget Approach for the Treatment of Alzheimer's Disease: Inhibition of Phosphodiesterase 9 (PDE9) and Histone Deacetylases (HDACs) Covering Diverse Selectivity Profiles>, Related Products of 89793-12-4, the main research area is Alzheimer’s disease HDAC inhibition PDE9 inhibition HDAC6 dual inhibitors; Alzheimer’s disease; HDAC6; dual inhibitors; histone deacetylase inhibition; phosphodiesterase 9 inhibition.

Here, we present a series of dual-target phosphodiesterase 9 (PDE9) and histone deacetylase (HDAC) inhibitors devised as pharmacol. tool compounds for assessing the implications of these two targets in Alzheimer’s disease (AD). These novel inhibitors were designed taking into account the key pharmacophoric features of known selective PDE9 inhibitors as well as privileged chem. structures, bearing zinc binding groups (hydroxamic acids and ortho-amino anilides) that hit HDAC targets. These substituents were selected according to rational criteria and previous knowledge from our group to explore diverse HDAC selectivity profiles (pan-HDAC, HDAC6 selective, and class I selective) that were confirmed in biochem. screens. Their functional response in inducing acetylation of histone and tubulin and phosphorylation of cAMP response element binding (CREB) was measured as a requisite for further progression into complete in vitro absorption, distribution, metabolism and excretion (ADME) and in vivo brain penetration profiling. Compound 31b, a selective HDAC6 inhibitor with acceptable brain permeability, was chosen for assessing in vivo efficacy of these first-in-class inhibitors, as well as studying their mode of action (MoA).

ACS Chemical Neuroscience published new progress about Alzheimer disease. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Related Products of 89793-12-4.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Li, Ruoxi; Ling, Dazheng; Tang, Tongke; Huang, Zhenghui; Wang, Manjiong; Ding, Yan; Liu, Taiping; Wei, Hanwen; Xu, Wenyue; Mao, Fei; Zhu, Jin; Li, Xiaokang; Jiang, Lubin; Li, Jian published the artcile< Discovery of Novel Plasmodium falciparum HDAC1 Inhibitors with Dual-Stage Antimalarial Potency and Improved Safety Based on the Clinical Anticancer Drug Candidate Quisinostat>, Safety of Ethyl 2-chloropyrimidine-5-carboxylate, the main research area is Plasmodium HDAC HDAC1 inhibitors antimalarials antitumor drug repurposing.

Previously, we identified the clin. anticancer drug candidate quisinostat as a novel and potent antimalarial lead compound To further enhance the antimalarial effect and improve safety, 31 novel spirocyclic hydroxamic acid derivatives were synthesized based on the structure of quisinostat, and their antimalarial activities and cytotoxicity were evaluated. Among them, compound 11 displayed broad potency in vitro against several multi-resistant malarial parasites, especially two artemisinin-resistant clin. isolates. Moreover, 11 could eliminate both liver and erythrocytic parasites in vivo, kill all morphol. erythrocytic parasites with specific potency against schizonts, and show acceptable metabolic stability and pharmacokinetic properties. Western blot anal., PfHDAC gene knockdown, and enzymic inhibition experiments collectively confirmed that PfHDAC1 was the target of 11. In summary, 11 is a structurally novel PfHDAC1 inhibitor with the potential to prevent and cure malaria, overcome multi-drug resistance, and provide a prospective prototype for antimalarial drug research.

Journal of Medicinal Chemistry published new progress about Acetylation (hyperacetylation). 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Safety of Ethyl 2-chloropyrimidine-5-carboxylate.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Takahashi, Bitoku; Ohta, Kiminori; Kawachi, Emiko; Fukasawa, Hiroshi; Hashimoto, Yuichi; Kagechika, Hiroyuki published the artcile< Novel Retinoid X Receptor Antagonists: Specific Inhibition of Retinoid Synergism in RXR-RAR Heterodimer Actions>, Related Products of 89793-12-4, the main research area is retinoid X receptor antagonist preparation cell differentiation obesity diabetes; pyrimidinecarboxylate RXR antagonist cell differentiation obesity diabetes.

Several 2-(arylamino)pyrimidine-5-carboxylic acids were designed as novel retinoid X receptor (RXR) antagonists. Two of the tested compounds alone did not exhibit differentiation-inducing activity toward HL-60 cells and did not affect the activity of a retinoic acid receptor (RAR) agonist, Am80, but did inhibit the synergistic activity of an RXR agonist, PA024, in the presence of Am80. The activity of these compounds was ascribed to selective antagonism at the RXR site of RXR-RAR heterodimers.

Journal of Medicinal Chemistry published new progress about Acute promyelocytic leukemia. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Related Products of 89793-12-4.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Zhang, Kehui; Lai, Fangfang; Lin, Songwen; Ji, Ming; Zhang, Jingbo; Zhang, Yan; Jin, Jing; Fu, Rong; Wu, Deyu; Tian, Hua; Xue, Nina; Sheng, Li; Zou, Xiaowen; Li, Yan; Chen, Xiaoguang; Xu, Heng published the artcile< Design, Synthesis, and Biological Evaluation of 4-Methyl Quinazoline Derivatives as Anticancer Agents Simultaneously Targeting Phosphoinositide 3-Kinases and Histone Deacetylases>, Synthetic Route of 89793-12-4, the main research area is quinazoline derivative anticancer phosphoinositide kinases histone deacetylase dual inhibitor.

Polypharmacol. is a promising paradigm in modern drug discovery. Herein, we have discovered a series of novel PI3K and HDAC dual inhibitors in which the hydroxamic acid moiety as the zinc binding functional group was introduced to a quinazoline-based PI3K pharmacophore through an appropriate linker. Systematic structure-activity relationship studies resulted in lead compounds 23 (shown in graphical abstract and duplicated as I) and 36 (II) that simultaneously inhibited PI3K and HDAC with nanomolar potencies and demonstrated favorable antiproliferative activities. Compounds 23 and 36 efficiently modulated the expression of p-AKT and Ac-H3, arrested the cell cycle, and induced apoptosis in HCT116 cancer cells. Following pharmacokinetic studies, 23 was further evaluated in HCT116 and HGC-27 xenograft models to show significant in vivo anticancer efficacies with tumor growth inhibitions of 45.8% (po, 150 mg/kg) and 62.6% (i.p., 30 mg/kg), resp. Overall, this work shows promise in discovering new anticancer therapeutics by the approach of simultaneously targeting PI3K and HDAC pathways with a single mol.

Journal of Medicinal Chemistry published new progress about Antitumor agents. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Synthetic Route of 89793-12-4.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Yang, Zhuang; Shen, Mingsheng; Tang, Minghai; Zhang, Wanhua; Cui, Xue; Zhang, Zihao; Pei, Heying; Li, Yong; Hu, Mengshi; Bai, Peng; Chen, Lijuan published the artcile< Discovery of 1,2,4-oxadiazole-Containing hydroxamic acid derivatives as histone deacetylase inhibitors potential application in cancer therapy>, Safety of Ethyl 2-chloropyrimidine-5-carboxylate, the main research area is oxadiazole hydroxamic acid preparation histone deacetylase inhibitor human cancer; 1,2,4-Oxadiazole; Anticancer; Antiproliferative; HDAC.

In this study, a series of novel HDAC inhibitors containing 1,2,4-oxadiazole as the cap group, were synthesized and evaluated in vitro. Compound I, displayed the most potent histone deacetylase (HDAC) inhibition, especially against HDAC1, 2, and 3 with IC50 values of 1.8, 3.6 and 3.0 nM, resp. In vitro antiproliferative studies confirmed that I was more potent than SAHA, with IC50 values against 12 types of cancer cell lines ranging from 9.8 to 44.9 nM. The results of Western blot assays showed that compound I can significantly up-regulate the acetylation of the biomarker his-H3 and mol. docking analyses revealed the mode of action of compound I against HDAC1. The results of flow-cytometry anal. suggested that the above compound induces cell cycle arrest at the G1 phase and has apoptotic effects and further investigation of the activity on the primary cells of three patients, showed IC50 values of 21.3, 61.1, and 77.4 nM. More importantly, an oral bioavailability of up to 53.52% was observed for compound I. An in vivo pharmacodynamic evaluation demonstrated that compound I can significantly inhibit tumor growth in a Daudi Burkitt’s lymphoma xenograft model, with tumor inhibition rates of 53.8 and 46.1% observed at 20 and 10 mg/kg when administered p.o. and i.v., resp. These results indicate that compound I may be a suitable lead for further evaluation and development as an HDAC inhibitors and potent anticancer agents.

European Journal of Medicinal Chemistry published new progress about Antitumor agents. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Safety of Ethyl 2-chloropyrimidine-5-carboxylate.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Takamatsu, Kayo; Takano, Atsushi; Yakushiji, Nobumasa; Morishita, Ken-ichi; Matsuura, Nobuyasu; Makishima, Makoto; Ali, Hamed Ismail; Akaho, Eiichi; Tai, Akihiro; Sasaki, Kenji; Kakuta, Hiroki published the artcile< Reduction of lipophilicity at the lipophilic domain of RXR agonists enables production of subtype preference: RXRα-preferential agonist possessing a sulfonamide moiety>, Formula: C7H7ClN2O2, the main research area is sulfonamide derivative preparation structure RXR agonist lipophilicity antitumor.

Retinoid X receptor agonists (RXR agonists, rexinoids) are interesting candidates for the treatment of cancers such as tamoxifen-resistant breast cancer and taxol-resistant lung cancer. However, well-known RXR agonists possess a strong lipophilic character. In addition, although RXR has three subtypes, no subtype-selective RXR agonists are known. Thus the authors aimed to produce less-lipophilic and subtype-selective RXR agonists. By designing sulfonamide-type RXR agonists, compound (I) was found to prefer RXRα over RXRβ and RXRγ, although the potency is less than the potencies of well-known RXR pan-agonists. Moreover, the results suggest that the reduction of lipophilicity at the hydrophobic interaction region of RXR agonists enables production of RXR subtype preference. The finding will be useful for the creation of more potent and less-lipophilic subtype-selective RXR agonists aimed at the reduction of undesirable side effects.

ChemMedChem published new progress about Homo sapiens. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Formula: C7H7ClN2O2.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Nunes, Joao; McGonagle, Grant A.; Eden, Jessica; Kiritharan, Girieshanie; Touzet, Megane; Lewell, Xiao; Emery, John; Eidam, Hilary; Harling, John D.; Anderson, Niall A. published the artcile< Targeting IRAK4 for Degradation with PROTACs>, Synthetic Route of 89793-12-4, the main research area is IRAK4 proteolysis targeted chimera PROTAC degradation cytokine.

Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) is a key mediator of innate immunity. IRAK4 overactivation is linked with several autoimmune diseases. To date, many IRAK4 inhibitors have been developed to block the protein’s kinase activity with the most advanced reaching Phase II clin. trials. Nevertheless, several reports suggest kinase activity is not disease-relevant in certain cell types, so removing scaffolding signaling in addition to IRAK4 kinase activity may offer a better therapeutic outcome. Herein, we describe the design and synthesis of an IRAK4 Proteolysis Targeted Chimera (PROTAC). We show that IRAK4 degradation induced by compound 9 leads to the inhibition of multiple cytokines in PBMCs. However, in IL-1β stimulated human dermal fibroblasts, inhibition of IL-6 and TNF-α release was not observed despite IRAK4 degradation Nonetheless, the possibility of targeting both IRAK4 kinase and scaffolding function could potentially lead to new therapeutic opportunities to treat autoimmune, inflammatory, and oncol. diseases.

ACS Medicinal Chemistry Letters published new progress about Autoimmune disease. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Synthetic Route of 89793-12-4.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Miah, Afjal H.; Smith, Ian E. D.; Rackham, Mark; Mares, Alina; Thawani, Aditya R.; Nagilla, Rakesh; Haile, Pamela A.; Votta, Bartholomew J.; Gordon, Laurie J.; Watt, Gillian; Denyer, Jane; Fisher, Don T.; Dace, Phoebe; Giffen, Paul; Goncalves, Andrea; Churcher, Ian; Scott-Stevens, Paul; Harling, John D. published the artcile< Optimization of a Series of RIPK2 PROTACs>, Synthetic Route of 89793-12-4, the main research area is PROTAC RIPK2 IAP binder drug optimization.

Receptor-interacting serine/threonine protein kinase 2 (RIPK2) is an important kinase of the innate immune system. Herein, we describe the optimization of a series of RIPK2 PROTACs which recruit members of the inhibitor of apoptosis (IAP) family of E3 ligases. Our PROTAC optimization strategy focused on reducing the lipophilicity of the early lead which resulted in the identification of analogs with improved solubility and increased human and rat microsomal stability. We identified a range of IAP binders that were successfully incorporated into potent RIPK2 PROTACs with attractive pharmacokinetic profiles. Compound 20 possessed the best overall profile with good solubility, potent degradation of RIPK2, and associated inhibition of TNFα release. A proof-of-concept study utilizing a slow release matrix demonstrated the feasibility of a long-acting parenteral formulation with >1 mo duration. This represents an attractive alternative dosing paradigm to oral delivery, especially for chronic diseases where compliance can be challenging.

Journal of Medicinal Chemistry published new progress about Blood. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Synthetic Route of 89793-12-4.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Rabal, Obdulia; Sanchez-Arias, Juan A.; Cuadrado-Tejedor, Mar; de Miguel, Irene; Perez-Gonzalez, Marta; Garcia-Barroso, Carolina; Ugarte, Ana; Estella-Hermoso de Mendoza, Ander; Saez, Elena; Espelosin, Maria; Ursua, Susana; Haizhong, Tan; Wei, Wu; Musheng, Xu; Garcia-Osta, Ana; Oyarzabal, Julen published the artcile< Discovery of in Vivo Chemical Probes for Treating Alzheimer's Disease: Dual Phosphodiesterase 5 (PDE5) and Class I Histone Deacetylase Selective Inhibitors>, Name: Ethyl 2-chloropyrimidine-5-carboxylate, the main research area is sildenafil vardenafil orthoaminoanilide synthesis antiAlzheimer SAR PDE5 histone deacetylase; Alzheimer’s disease; PDE5 inhibition; chemical probes; class I HDAC selective inhibition; dual inhibitors; in vivo test.

In order to determine the contributions of histone deacetylase (HDAC) isoforms to the beneficial effects of dual phosphodiesterase 5 (PDE5) and pan-HDAC inhibitors on in vivo models of Alzheimer’s disease (AD), we have designed, synthesized, and tested novel chem. probes with the desired target compound profile of PDE5 and class I HDAC selective inhibitors. Compared to previous hydroxamate-based series, these mols. exhibit longer residence times on HDACs. In this scenario, shorter or longer preincubation times may have a significant impact on the IC50 values of these compounds and therefore on their corresponding selectivity profiles on the different HDAC isoforms. On the other hand, different chem. series have been explored and, as expected, some pairwise comparisons show a clear impact of the scaffold on biol. responses. The lead identification process led to compound I, which shows an adequate ADME-Tox profile and in vivo target engagement (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation) in the central nervous system (CNS), suggesting that this compound represents an optimized chem. probe; thus, I has been assayed in a mouse model of AD (Tg2576).

ACS Chemical Neuroscience published new progress about Alzheimer disease. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Name: Ethyl 2-chloropyrimidine-5-carboxylate.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia