Month: February 2023

Discovery of Potent and Orally Effective Dual Janus Kinase 2/FLT3 Inhibitors for the Treatment of Acute Myelogenous Leukemia and Myeloproliferative Neoplasms was written by Yang, Tao;Hu, Mengshi;Qi, Wenyan;Yang, Zhuang;Tang, Minghai;He, Jun;Chen, Yong;Bai, Peng;Yuan, Xue;Zhang, Chufeng;Liu, Kongjun;Lu, Yulin;Xiang, Mingli;Chen, Lijuan. And the article was included in Journal of Medicinal Chemistry in 2019.Safety of tert-Butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate This article mentions the following:

Herein, the design, synthesis, and structure-activity relationships of a series of unique 4-(1H-pyrazol-4-yl)-pyrimidin-2-amine derivatives that selectively inhibit Janus kinase 2 (JAK2) and FLT3 kinases is described. These screening cascades revealed that I was a preferred compound with IC₅₀ values of 0.7 and 4 nM for JAK2 and FLT3, resp. Moreover, I was a potent JAK2 inhibitor with 37-fold and 56-fold selectivity over JAK1 and JAK3, resp., and possessed an excellent selectivity profile over the other 100 representative kinases. In a series of cytokine-stimulated cell-based assays, I exhibited a higher JAK2 selectivity over other JAK isoforms. The oral administration of 60 mg/kg of I could significantly inhibit tumor growth, with a tumor growth inhibition rate of 93 and 85% in MV4-11 and SET-2 xenograft models, resp. Addnl., I showed an excellent bioavailability (F = 58%), a suitable half-life time (T_1/2 = 4.1 h), a satisfactory metabolic stability, and a weak CYP3A4 inhibitory activity, suggesting that I might be a potential drug candidate for JAK2-driven myeloproliferative neoplasms and FLT3-internal tandem duplication-driven acute myelogenous leukemia. In the experiment, the researchers used many compounds, for example, tert-Butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate (cas: 154590-34-8Safety of tert-Butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate).

tert-Butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate (cas: 154590-34-8) belongs to piperazine derivatives. Simple N-substituted piperazines have been found in many drug molecules. Piperazine is an anthelminthic especially useful in the treatment of partial intestinal obstruction caused by Ascaris worms, which is a condition primarily seen in children. Piperazine hydrate and piperazine citrate are the main anthelminthic piperazines.Safety of tert-Butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

Evaluation of cariprazine in the treatment of bipolar I and II depression: a randomized, double-blind, placebo-controlled, phase 2 trial. was written by Yatham, Lakshmi N;Vieta, Eduard;Earley, Willie. And the article was included in International clinical psychopharmacology in 2020.Formula: C21H32Cl2N4O This article mentions the following:

This double-blind placebo-controlled, fixed/flexible-dose phase 2 trial assessed the efficacy, safety, and tolerability of cariprazine vs. placebo for depressive episodes associated with bipolar I or II disorder. Primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total scores (baseline to week 8), and secondary endpoint was mean Clinical Global Impressions-Improvement score (week 8). Patients were randomized (N = 233) 1:1:1 to placebo, ‘low-dose’ 0.25-0.5 mg/day or ‘high-dose’ 1.5-3.0 mg/day cariprazine. Adverse events, laboratory results, vital signs, extrapyramidal symptoms, and suicide risk were monitored. Neither cariprazine group significantly separated from placebo in primary (mixed-effect model repeated measures MADRS least-squares mean differences: low-dose = -0.7, P = 0.7408; high-dose = 0.0, P = 0.9961) or secondary efficacy measures. No new safety signals with cariprazine were observed and common treatment-emergent adverse events (≥5% of cariprazine patients and twice the rate of placebo) included insomnia, akathisia, dry mouth, nausea, weight increased, diarrhea, restlessness, vomiting, musculoskeletal stiffness, migraine, and cough. Metabolic and weight changes were generally similar for cariprazine and placebo. Factors that may have affected the outcome of the trial were identified, which helped to inform the design and conduct of subsequent phase 2b/3 clinical trials of cariprazine in bipolar depression. In the experiment, the researchers used many compounds, for example, 3-(trans-4-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea (cas: 839712-12-8Formula: C21H32Cl2N4O).

3-(trans-4-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea (cas: 839712-12-8) belongs to piperazine derivatives. Piperazine causes primary dermal irritation and skin burns at high concentrations. Piperazine also causes eye irritation in humans. Two common salts in the form of which piperazine is usually prepared for pharmaceutical or veterinary purposes are the citrate, 3C4H10N2.2C6H8O7 (i.e. containing 3 molecules of piperazine to 2 molecules of citric acid), and the adipate, C4H10N2.C6H10O4 (containing 1 molecule each of piperazine and adipic acid).Formula: C21H32Cl2N4O

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

Hemiplegic migraine type 2 with new mutation of the ATP1A2 gene in Japanese cases was written by Oda, Ituki;Danno, Daisuke;Saigoh, Kazumasa;Wolf, Johanna;Kawashita, Norihito;Hirano, Makito;Samukawa, Makoto;Kitamura, Shigekazu;Kikui, Shoji;Takeshima, Takao;Mitsui, Yoshiyuki;Kusunoki, Susumu;Nagai, Yoshitaka. And the article was included in Neuroscience Research (Shannon, Ireland) in 2022.Electric Literature of C27H32Cl2F2N2O3 This article mentions the following:

We analyzed the clin. symptoms of hemiplegic migraine (HM) and their relevance in four Japanese patients considered to have ATP1A2 mutations as a cause. Sequencing of ATP1A2 was performed using the Sanger method in 43 blood samples from clin. suspected patients with familial HM. Subsequently, algorithm anal., allele frequency determination, and three-dimensional structure anal. of the recognized variants were performed, and the recognized variants were evaluated. We found four heterozygous missense mutations in ATP1A2 (Case 1: p.R51C; Case 2: p.R65L; Case 3: p.A269P; Case 4: p.D999H), three of which had not been reported to date. These four mutations may also affect the structure of the protein products, as assessed using a three-dimensional structural anal. In all four cases, the clin. symptoms included visual, sensory, motor, and verbal symptoms and the frequency and duration of headache attacks varied. Addnl., oral administration of a combination of lomerizine hydrochloride and topiramate had a partial effect in three cases. We report four missense mutations in ATP1A2. This report will be useful for the future anal. of mutations and clin. types in Asians, as well as Westerners, with migraine. In the experiment, the researchers used many compounds, for example, 1-(Bis(4-fluorophenyl)methyl)-4-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride (cas: 101477-54-7Electric Literature of C27H32Cl2F2N2O3).

1-(Bis(4-fluorophenyl)methyl)-4-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride (cas: 101477-54-7) belongs to piperazine derivatives. Piperazine belongs to the family of medicines called anthelmintics. Piperazines are very broad chemical group, covering a wide range of drugs from antidepressants to antihistamines. The connecting property of all these chemicals is the presence of a piperazine functional group.Electric Literature of C27H32Cl2F2N2O3

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

Simultaneous determination of tandospirone and its active metabolite, 1-[2-pyrimidyl]-piperazine in rat plasma by LC-MS/MS and its application to a pharmacokinetic study was written by Hu, Wenya;Jia, Mi;He, Siyan;Xie, Huiru;Jiang, Xuehua;Wang, Ling. And the article was included in Biomedical Chromatography in 2019.Category: piperazines This article mentions the following:

A rapid, sensitive and selective liquid chromatog.-tandem mass spectrometry method for the detection of tandospirone (TDS) and its active metabolite 1-[2-pyrimidyl]-piperazine (1-PP) in Sprague-Dawley rat plasma is described. It was employed in a pharmacokinetic study. These analytes and the internal standards were extracted from plasma using protein precipitation with acetonitrile, then separated on a CAPCELL PAK ADME C₁₈ column using a mobile phase of acetonitrile and 5 mM ammonium formate acidified with formic acid (0.1%, volume/volume) at a total flow rate of 0.4 mL/min. The detection was performed with a tandem mass spectrometer equipped with an electrospray ionization source. The method was validated to quantify the concentration ranges of 1.000-500.0 ng/mL for TDS and 10.00-500.0 ng/mL for 1-PP. Total time for each chromatograph was 3.0 min. The intra-day precision was between 1.42 and 6.69% and the accuracy ranged from 95.74 to 110.18% for all analytes. Inter-day precision and accuracy ranged from 2.47 to 6.02% and from 98.37 to 105.62%, resp. The lower limits of quantification were 1.000 ng/mL for TDS and 10.00 ng/mL for 1-PP. This method provided a fast, sensitive and selective anal. tool for quantification of tandospirone and its metabolite 1-PP in plasma necessary for the pharmacokinetic investigation. In the experiment, the researchers used many compounds, for example, rel-(3aR,4S,7R,7aS)-2-(4-(4-(Pyrimidin-2-yl)piperazin-1-yl)butyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione 2-hydroxypropane-1,2,3-tricarboxylate (cas: 112457-95-1Category: piperazines).

rel-(3aR,4S,7R,7aS)-2-(4-(4-(Pyrimidin-2-yl)piperazin-1-yl)butyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione 2-hydroxypropane-1,2,3-tricarboxylate (cas: 112457-95-1) belongs to piperazine derivatives. The piperazine scaffold is often found in biologically active compounds in different therapeutic areas. These therapeutic areas include antifungals, antidepressants, antivirals, and serotonin receptor (5-HT) antagonists/agonists. Piperazine and its salts did not induce point mutations in a bacterial test. A series of mutagenicity studies in cells, both in vitro and in vivo, has been completed and showed no evidence of mutagenic effect.Category: piperazines

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

A theoretical entropy score as a single value to express inhibitor selectivity was written by Uitdehaag, Joost C. M.;Zaman, Guido J. R.. And the article was included in BMC Bioinformatics in 2011.Related Products of 692737-80-7 This article mentions the following:

Designing maximally selective ligands that act on individual targets is the dominant paradigm in drug discovery. Poor selectivity can underlie toxicity and side effects in the clinic, and for this reason compound selectivity is increasingly monitored from very early on in the drug discovery process. To make sense of large amounts of profiling data, and to determine when a compound is sufficiently selective, there is a need for a proper quant. measure of selectivity. Here we propose a new theor. entropy score that can be calculated from a set of IC₅₀ data. In contrast to previous measures such as the ‘selectivity score’, Gini score, or partition index, the entropy score is non-arbitary, fully exploits IC₅₀ data, and is not dependent on a reference kinase. In addition, the entropy score gives the most robust values with data from different sources, because it is less sensitive to errors. We apply the new score to kinase and nuclear receptor profiling data, and to high-throughput screening data. In addition, through analyzing profiles of clin. compounds, we show that a more selective inhibitor is not necessarily more drug-like. For quantifying selectivity from panel profiling, a theor. entropy score is the best method. It is valuable for studying the mol. mechanisms of selectivity, and to steer compound progression in drug discovery programs. In the experiment, the researchers used many compounds, for example, 4-Amino-5-fluoro-3-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)quinolin-2(1H)-one 2-hydroxypropanoate (cas: 692737-80-7Related Products of 692737-80-7).

4-Amino-5-fluoro-3-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)quinolin-2(1H)-one 2-hydroxypropanoate (cas: 692737-80-7) belongs to piperazine derivatives. Piperazine was first introduced as an anthelmintic in 1953. Piperazine compounds mediate their anthelmintic action by generally paralyzing parasites, allowing the host body to easily remove or expel the invading organism. Piperazine and its salts did not induce point mutations in a bacterial test. A series of mutagenicity studies in cells, both in vitro and in vivo, has been completed and showed no evidence of mutagenic effect.Related Products of 692737-80-7

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

Combination of miR-143 and miR-506 reduces lung and pancreatic cancer cell growth through the downregulation of cyclin-dependent kinases was written by Hossian, A. k. m. nawshad;Mackenzie, Gerardo g.;Mattheolabakis, George. And the article was included in Oncology Reports in 2021.Reference of 1211441-98-3 This article mentions the following:

Lung cancer (LC) and pancreatic cancer (PC) are the first and fourth leading causes of cancer-related deaths in the US. Deregulated cell cycle progression is the cornerstone for rapid cell proliferation, tumor development, and progression. Here, we provide evidence that a novel combinatorial miR treatment inhibits cell cycle progression at two phase transitions, through their activity on the CDK4 and CDK1 genes. Following transfection with miR-143 and miR-506, we analyzed the differential gene expression of CDK4 and CDK1, using qPCR or western blot anal., and evaluated cell cycle inhibition, apoptosis and cytotoxicity. The combinatorial miR-143/506 treatment downregulated CDK4 and CDK1 levels, and induced apoptosis in LC cells, while sparing normal lung fibroblasts. Moreover, the combinatorial miR treatment demonstrated a comparable activity to clin. tested cell cycle inhibitors in inhibiting cell cycle progression, by presenting substantial inhibition at the G1/S and G2/M cell cycle transitions. More importantly, the miR-143/506 treatment presented a broader application, effectively downregulating CDK1 and CDK4 levels, and reducing cell growth in PC cells. These findings suggest that the miR-143/506 combination acts as a promising approach to inhibit cell cycle progression for cancer treatment with minimal toxicity to normal cells. In the experiment, the researchers used many compounds, for example, 7-Cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (cas: 1211441-98-3Reference of 1211441-98-3).

7-Cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (cas: 1211441-98-3) belongs to piperazine derivatives. Piperazine causes primary dermal irritation and skin burns at high concentrations. Piperazine also causes eye irritation in humans. Outside the body, piperazine has a remarkable power to dissolve uric acid and producing a soluble urate, but in clinical experience it has not proved equally successful. Reference of 1211441-98-3

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

Revealing the Unbinding Kinetics and Mechanism of Type I and Type II Protein Kinase Inhibitors by Local-Scaled Molecular Dynamics Simulations was written by Du, Yu;Wang, Renxiao. And the article was included in Journal of Chemical Theory and Computation in 2020.COA of Formula: C26H33N5O3 This article mentions the following:

Protein kinase inhibitors disrupt phosphorylation of the target kinases, which are an important class of drug for treating cancer and other diseases. Conventional structure-based design methods (such as mol. docking) focus on the static binding mode of the kinase inhibitor with its target. However, dissociation kinetic properties of a drug mol. are found to correlate with its residence time in vivo and thus have drawn the attention of drug designers in recent years. In this study, we have applied the local-scaled mol. dynamics (MD) simulation enabled in GROMACS software to explore the unbinding mechanism of a total of 41 type I and type II kinase inhibitors. Our simulation considered multiple starting configurations as well as possible protonation states of kinase inhibitors. Based on our local-scaled MD results, we discovered that the integrals of the favorable binding energy during dissociation correlated well (R² = 0.64) with the exptl. dissociation rate constants of those kinase inhibitors on the entire data set. Given its accuracy and tech. advantage, this method may serve as a practical option for estimating this important property in reality. Our simulation also provided a reasonable explanation of the dynamic properties of kinase and its inhibitor as well as the role of relevant water mols. in dissociation In the experiment, the researchers used many compounds, for example, rel-N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide (cas: 1035270-39-3COA of Formula: C26H33N5O3).

rel-N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide (cas: 1035270-39-3) belongs to piperazine derivatives. Piperazine is a fairly basic compound and is an amine solvent. Intermediate for a wide range of pharmaceuticals, polymers, dyes, corrosion inhibitors, rubber accelerators and surfactants.COA of Formula: C26H33N5O3

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

HMG-CoA Reductase Inhibitor Statins Activate the Transcriptional Activity of p53 by Regulating the Expression of TAZ was written by Miyajima, Chiharu;Hayakawa, Yurika;Inoue, Yasumichi;Nagasaka, Mai;Hayashi, Hidetoshi. And the article was included in Pharmaceuticals in 2022.HPLC of Formula: 548472-68-0 This article mentions the following:

Transcriptional coactivator with PDZ-binding motif (TAZ) is a downstream transcriptional regulator of the Hippo pathway that controls cell growth and differentiation. The aberrant activation of TAZ correlates with a poor prognosis in human cancers, such as breast and colon cancers. We previously demonstrated that TAZ inhibited the tumor suppressor functions of p53 and enhanced cell proliferation. Statins, which are used to treat dyslipidemia, have been reported to suppress the activity of TAZ and exert anti-tumor effects. In the present study, we focused on the regulation of p53 functions by TAZ and investigated whether statins modulate these functions via TAZ. The results obtained suggest that statins, such as simvastatin and fluvastatin, activated the transcriptional function of p53 by suppressing TAZ protein expression. Furthermore, co-treatment with simvastatin and anti-tumor agents that cooperatively activate p53 suppressed cancer cell survival. These results indicate a useful mechanism by which statins enhance the effects of anti-tumor agents through the activation of p53 and may represent a novel approach to cancer therapy. In the experiment, the researchers used many compounds, for example, 4-(cis-4,5-Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)piperazin-2-one (cas: 548472-68-0HPLC of Formula: 548472-68-0).

4-(cis-4,5-Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)piperazin-2-one (cas: 548472-68-0) belongs to piperazine derivatives. Industrial applications of piperazine include the manufacture of plastics, resins, pesticides and brake fluids. Although many piperazine derivatives occur naturally, piperazine itself can be synthesized by reacting alcoholic ammonia with 1,2-dichloroethane, by the action of sodium and ethylene glycol on ethylene diamine hydrochloride, or by reduction of pyrazine with sodium in ethanol.HPLC of Formula: 548472-68-0

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

Synthesis of the third comonomer of Kevlar 1414, p,p’-diaminophenylpiperazine was written by Hong, Youji;Xiao, Ruojian;Ye, Xiuzhen. And the article was included in Huadong Fangzhi Gongxueyuan Xuebao in 1985.Name: 4,4′-(Piperazine-1,4-diyl)dianiline This article mentions the following:

Piperazine  [110-85-0] was treated with p-ClC₆H₄NO₂  [100-00-5] in N-methylpyrolidone in the presence of CaH₂ to give 1,4-bis(p-nitrophenyl)piperazine (I) [16264-05-4] with productivity <82.3%, compared with 57.9% without CaH₂. I was refluxed with SnCl₂, 95% EtOH, and concentrated HCl for 2 h to give 1,4-bis(p-aminophenyl)piperazine  [7479-12-1] in 80.6% yield. In the experiment, the researchers used many compounds, for example, 4,4′-(Piperazine-1,4-diyl)dianiline (cas: 7479-12-1Name: 4,4′-(Piperazine-1,4-diyl)dianiline).

4,4′-(Piperazine-1,4-diyl)dianiline (cas: 7479-12-1) belongs to piperazine derivatives. Simple N-substituted piperazines have been found in many drug molecules. Piperazines are very broad chemical group, covering a wide range of drugs from antidepressants to antihistamines. The connecting property of all these chemicals is the presence of a piperazine functional group.Name: 4,4′-(Piperazine-1,4-diyl)dianiline

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

Research progress of 70 kDa ribosomal protein S6 kinase (P70S6K) inhibitors as effective therapeutic tools for obesity, type II diabetes and cancer was written by Zhang, Na;Ma, Shutao. And the article was included in Current Medicinal Chemistry in 2020.Reference of 1255517-76-0 This article mentions the following:

At present, diseases such as obesity, type II diabetes and cancer have brought serious health problems, which are closely related to mTOR pathway. 70 kDa ribosomal protein S6 kinase (p70S6K), as a significant downstream effector of mTOR, mediates protein synthesis, RNA processing, glucose homeostasis, cell growth and apoptosis. Inhibiting the function of p70S6K can reduce the risk of obesity which helps to treat dyslipidemia, enhance insulin sensitivity, and extend the life span of mammals. Therefore, p70S6K has become a potential target for the treatment of these diseases. So far, except for the first p70S6K specific inhibitor PF-4708671 developed by Pfizer and LY2584702 developed by Lilai, all of them are in preclin. research. This paper briefly introduces the general situation of p70S6K and reviews their inhibitors in recent years, which are mainly classified into two categories: natural compounds and synthetic compounds In particular, their inhibitory activities, structure-activity relationships (SARs) and mechanisms are highlighted. In the experiment, the researchers used many compounds, for example, 2-((4-(5-Ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (cas: 1255517-76-0Reference of 1255517-76-0).

2-((4-(5-Ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (cas: 1255517-76-0) belongs to piperazine derivatives. Industrial applications of piperazine include the manufacture of plastics, resins, pesticides and brake fluids. Although many piperazine derivatives occur naturally, piperazine itself can be synthesized by reacting alcoholic ammonia with 1,2-dichloroethane, by the action of sodium and ethylene glycol on ethylene diamine hydrochloride, or by reduction of pyrazine with sodium in ethanol.Reference of 1255517-76-0

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics