Day: October 19, 2022

《Structure-Activity Relationship Study of Covalent Pan-phosphatidylinositol 5-Phosphate 4-Kinase Inhibitors》 was written by Manz, Theresa D.; Sivakumaren, Sindhu C.; Yasgar, Adam; Hall, Matthew D.; Davis, Mindy I.; Seo, Hyuk-Soo; Card, Joseph D.; Ficarro, Scott B.; Shim, Hyeseok; Marto, Jarrod A.; Dhe-Paganon, Sirano; Sasaki, Atsuo T.; Boxer, Matthew B.; Simeonov, Anton; Cantley, Lewis C.; Shen, Min; Zhang, Tinghu; Ferguson, Fleur M.; Gray, Nathanael S.. Recommanded Product: 1193-21-1 And the article was included in ACS Medicinal Chemistry Letters in 2020. The article conveys some information:

Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are important mol. players in a variety of diseases, such as cancer. Currently available PI5P4K inhibitors are reversible small mols., which may lack selectivity and sufficient cellular on-target activity. In this study, we present a new class of covalent pan-PI5P4K inhibitors with potent biochem. and cellular activity. Our designs are based on THZ-P1-2, a covalent PI5P4K inhibitor previously developed in our laboratory Here, we report further structure-guided optimization and structure-activity relationship (SAR) study of this scaffold, resulting in compound 30(I), which retained biochem. and cellular potency, while demonstrating a significantly improved selectivity profile. Furthermore, we confirm that the inhibitors show efficient binding affinity in the context of HEK 293T cells using isothermal CETSA methods. Taken together, I represents a highly selective pan-PI5P4K covalent lead mol. In the experiment, the researchers used 4,6-Dichloropyrimidine(cas: 1193-21-1Recommanded Product: 1193-21-1)

4,6-Dichloropyrimidine(cas: 1193-21-1) is a member of organic chlorides. Organic chloride content in crude oil can be detected through specialized laboratory analysis. Care and attention are essential while sampling and testing.Recommanded Product: 1193-21-1

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Feng, Da; Zuo, Xiaofang; Jing, Lanlan; Chen, Chin-Ho; Olotu, Fisayo A.; Lin, Hao; Soliman, Mahmoud; De Clercq, Erik; Pannecouque, Christophe; Lee, Kuo-Hsiung; Kang, Dongwei; Liu, Xinyong; Zhan, Peng published their research in European Journal of Medicinal Chemistry in 2021. The article was titled 《Design, synthesis, and evaluation of “”dual-site””-binding diarylpyrimidines targeting both NNIBP and the NNRTI adjacent site of the HIV-1 reverse transcriptase》.Product Details of 3934-20-1 The article contains the following contents:

To improve the drug-resistance profiles of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a novel series of “”dual-site”” binding diarylpyrimidine (DAPY) derivatives I [R1 = H, cyclopropyl, propargyl, etc.] and II [X = 1-R2-piperidin-4-yl, 1-R2-piperidin-4-ylmethyl, 1-R2-pyrrolidin-3-yl; R2 = methylsulfonyl, trifluoromethylsulfonyl, trifluoromethylcarbonyl, etc.] targeting both the NNRTI adjacent site and NNRTIs binding pocket (NNIBP) were designed, synthesized and evaluated for their anti-HIV potency in TZM-bl and MT-4 cells. Eight compounds I and II exhibited moderate to excellent potencies in inhibiting wild-type (WT) HIV-1 replication with EC50 values ranging from 2.45 nM to 5.36 nM, and I [R1 = propargylamino] (EC50 = 2.45 nM) proved to be the most promising inhibitor. Of note, I [R1 = propargylamino] exhibited potent activity against the single mutant strain E138K (EC50 = 10.6 nM), being comparable with ETR (EC50 = 9.80 nM) and 3.5-fold more potent than that of morpholino pyrimidine compound (EC50 = 37.3 nM). Moreover, I [R1 = propargylamino] acted as a classical NNRTI with high affinity for WT HIV-1 RT (IC50 = 0.0589μM). The detailed structure-activity relationships (SARs) of the representative compounds were also determined, and further supported by mol. dynamics simulation. Overall, the “”dual-site””-binding NNRTIs have significant prospects and pave the way for the next round of rational design of potent anti-HIV-1 agents. In the experiment, the researchers used 2,4-Dichloropyrimidine(cas: 3934-20-1Product Details of 3934-20-1)

2,4-Dichloropyrimidine(cas: 3934-20-1) is a member of organic chlorides. Organic chloride content in crude oil can be detected through specialized laboratory analysis. Care and attention are essential while sampling and testing.Product Details of 3934-20-1

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Jin, Xin; Piao, Hu-Ri; Pannecouque, Christophe; De Clercq, Erik; Zhuang, Chunlin; Chen, Fen-Er published an article in 2021. The article was titled 《Design of the naphthyl-diarylpyrimidines as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) via structure-based extension into the entrance channel》, and you may find the article in European Journal of Medicinal Chemistry.Application of 3764-01-0 The information in the text is summarized as follows:

A series of novel naphthyl-diarylpyrimidine (DAPY) derivatives were designed and synthesized to explore the entrance channel of the non-nucleoside reverse transcriptase inhibitors binding pocket (NNIBP) by incorporating different flexible side chains at the C-6 position. The biol. evaluation results showed that all analogs possessed promising HIV-1 inhibitory activity at the nanomolar concentration range. Three compounds (7, 9 and 39) displayed excellent potency against WT HIV-1 strain with EC50 values ranging from 5 to 10 nM and high selectivity indexes (SI = 3504, 30488 and 22846, resp.), which were higher than for nevirapine and comparable to the values for etravirine. The RT inhibition activity, preliminary structure-activity relationship and mol. docking study showed that the side chain at the C-6 position of the DAPYs occupied the entrance channel and significantly influenced anti-HIV activity and selectivity. Addnl., the physicochem. properties were investigated to evaluate the drug-like features, which indicated that introducing various substituents on the pyrimidine ring can improve solubility In the experiment, the researchers used many compounds, for example, 2,4,6-Trichloropyrimidine(cas: 3764-01-0Application of 3764-01-0)

2,4,6-Trichloropyrimidine(cas: 3764-01-0) is a member of organic chlorides. Organic chloride content in crude oil can be detected through specialized laboratory analysis. Care and attention are essential while sampling and testing.Application of 3764-01-0

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

In 2022,Hopkins, Brian T.; Bame, Eris; Bajrami, Bekim; Black, Cheryl; Bohnert, Tonika; Boiselle, Carrie; Burdette, Doug; Burns, Jeremy C.; Delva, Luisette; Donaldson, Douglas; Grater, Richard; Gu, Chungang; Hoemberger, Marc; Johnson, Josh; Kapadnis, Sudarshan; King, Kris; Lulla, Mukesh; Ma, Bin; Marx, Isaac; Magee, Tom; Meissner, Robert; Metrick, Claire M.; Mingueneau, Michael; Murugan, Paramasivam; Otipoby, Kevin L.; Polack, Evelyne; Poreci, Urjana; Prince, Robin; Roach, Allie M.; Rowbottom, Chris; Santoro, Joseph C.; Schroeder, Patricia; Tang, Hao; Tien, Eric; Zhang, Fengmei; Lyssikatos, Joseph published an article in Journal of Medicinal Chemistry. The title of the article was 《Discovery and Preclinical Characterization of BIIB091, a Reversible, Selective BTK Inhibitor for the Treatment of Multiple Sclerosis》.Application In Synthesis of 2,4-Dichloropyrimidine The author mentioned the following in the article:

Multiple Sclerosis is a chronic autoimmune neurodegenerative disorder of the central nervous system (CNS) that is characterized by inflammation, demyelination, and axonal injury leading to permeant disability. In the early stage of MS, inflammation is the primary driver of the disease progression. There remains an unmet need to develop high efficacy therapies with superior safety profiles to prevent the inflammation processes leading to disability. Herein, we describe the discovery of BIIB091 (I), a structurally distinct orthosteric ATP competitive, reversible inhibitor that binds the BTK protein in a DFG-in confirmation designed to sequester Tyr-551, an important phosphorylation site on BTK, into an inactive conformation with excellent affinity. Preclin. studies demonstrated BIB091 to be a high potency mol. with good drug-like properties and a safety/tolerability profile suitable for clin. development as a highly selective, reversible BTKi for treating autoimmune diseases such as MS. In the experiment, the researchers used 2,4-Dichloropyrimidine(cas: 3934-20-1Application In Synthesis of 2,4-Dichloropyrimidine)

2,4-Dichloropyrimidine(cas: 3934-20-1) is a member of organic chlorides. Almost all organochlorine compounds are synthesized. It is widely used as intermediates, solvents and pesticides of chemical synthetic products.Application In Synthesis of 2,4-Dichloropyrimidine

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

In 2022,Boffey, Helen K.; Rooney, Timothy P. C.; Willems, Henriette M. G.; Edwards, Simon; Green, Christopher; Howard, Tina; Ogg, Derek; Romero, Tamara; Scott, Duncan E.; Winpenny, David; Duce, James; Skidmore, John; Clarke, Jonathan H.; Andrews, Stephen P. published an article in Journal of Medicinal Chemistry. The title of the article was 《Development of Selective Phosphatidylinositol 5-Phosphate 4-Kinase γ Inhibitors with a Non-ATP-competitive, Allosteric Binding Mode》.HPLC of Formula: 90213-66-4 The author mentioned the following in the article:

Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are emerging as attractive therapeutic targets in diseases, such as cancer, immunol. disorders, and neurodegeneration, owing to their central role in regulating cell signaling pathways that are either dysfunctional or can be modulated to promote cell survival. Different modes of binding may enhance inhibitor selectivity and reduce off-target effects in cells. Here, we describe efforts to improve the physicochem. properties of the selective PI5P4Kγ inhibitor, NIH-12848 (1). These improvements enabled the demonstration that this chemotype engages PI5P4Kγ in intact cells and that compounds from this series do not inhibit PI5P4Kα or PI5P4Kβ. Furthermore, the first X-ray structure of PI5P4Kγ bound to an inhibitor has been determined with this chemotype, confirming an allosteric binding mode. An exemplar from this chem. series adopted two distinct modes of inhibition, including through binding to a putative lipid interaction site which is 18 Å from the ATP pocket.2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine(cas: 90213-66-4HPLC of Formula: 90213-66-4) was used in this study.

2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine(cas: 90213-66-4) belongs to pyrimidine. The pyrimidine ring system has wide occurrence in nature as substituted and ring fused compounds and derivatives, including the nucleotides cytosine, thymine and uracil, thiamine (vitamin B1) and alloxan. HPLC of Formula: 90213-66-4

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Related Products of 3764-01-0In 2016 ,《Trisubstituted Pyrimidines as Efficacious and Fast-Acting Antimalarials》 appeared in Journal of Medicinal Chemistry. The author of the article were Norcross, Neil R.; Baragana, Beatriz; Wilson, Caroline; Hallyburton, Irene; Osuna-Cabello, Maria; Norval, Suzanne; Riley, Jennifer; Stojanovski, Laste; Simeons, Frederick R. C.; Porzelle, Achim; Grimaldi, Raffaella; Wittlin, Sergio; Duffy, Sandra; Avery, Vicky M.; Meister, Stephan; Sanz, Laura; Jimenez-Diaz, Belen; Angulo-Barturen, Inigo; Ferrer, Santiago; Martinez, Maria Santos; Gamo, Francisco Javier; Frearson, Julie A.; Gray, David W.; Fairlamb, Alan H.; Winzeler, Elizabeth A.; Waterson, David; Campbell, Simon F.; Willis, Paul; Read, Kevin D.; Gilbert, Ian H.. The article conveys some information:

In this paper we describe the optimization of a phenotypic hit against Plasmodium falciparum, based on a trisubstituted pyrimidine scaffold. This led to compounds with good pharmacokinetics and oral activity in a P. berghei mouse model of malaria. The most promising compound I showed a reduction in parasitemia of 96% when dosed at 30 mg/kg orally once a day for 4 days in the P. berghei mouse model of malaria. It also demonstrated a rapid rate of clearance of the erythrocytic stage of P. falciparum in the SCID mouse model with an ED90 of 11.7 mg/kg when dosed orally. Unfortunately, the compound is a potent inhibitor of cytochrome P 450 enzymes, probably due to a 4-pyridyl substituent. Nevertheless, this is a lead mol. with a potentially useful antimalarial profile, which could either be further optimized or be used for target hunting.2,4,6-Trichloropyrimidine(cas: 3764-01-0Related Products of 3764-01-0) was used in this study.

2,4,6-Trichloropyrimidine(cas: 3764-01-0) is a member of organic chlorides. Organic chlorides are compounds containing a carbon-chlorine bond, which are widely used in the oil field as a wax dissolver. They are generally not present in crude oils and are typically the result of additives, cleaning solutions or chemicals used for oil recovery.Related Products of 3764-01-0

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Recommanded Product: 3934-20-1In 2021 ,《Discovery of ASTX029, A Clinical Candidate Which Modulates the Phosphorylation and Catalytic Activity of ERK1/2》 was published in Journal of Medicinal Chemistry. The article was written by Heightman, Tom D.; Berdini, Valerio; Bevan, Luke; Buck, Ildiko M.; Carr, Maria G.; Courtin, Aurelie; Coyle, Joseph E.; Day, James E. H.; East, Charlotte; Fazal, Lynsey; Griffiths-Jones, Charlotte M.; Howard, Steven; Kucia-Tran, Justyna; Martins, Vanessa; Muench, Sandra; Munck, Joanne M.; Norton, David; O’Reilly, Marc; Palmer, Nicholas; Pathuri, Puja; Peakman, Torren M.; Reader, Michael; Rees, David C.; Rich, Sharna J.; Shah, Alpesh; Wallis, Nicola G.; Walton, Hugh; Wilsher, Nicola E.; Woolford, Alison J.-A.; Cooke, Michael; Cousin, David; Onions, Stuart; Shannon, Jonathan; Watts, John; Murray, Christopher W.. The article contains the following contents:

Aberrant activation of the mitogen-activated protein kinase pathway frequently drives tumor growth, and the ERK1/2 kinases are positioned at a key node in this pathway, making them important targets for therapeutic intervention. Recently, a number of ERK1/2 inhibitors have been advanced to investigational clin. trials in patients with activating mutations in B-Raf proto-oncogene or Ras. Here, we describe the discovery of the clin. candidate ASTX029 (15)(I) through structure-guided optimization of our previously published isoindolinone lead (7). The medicinal chem. campaign focused on addressing CYP3A4-mediated metabolism and maintaining favorable physicochem. properties. These efforts led to the identification of ASTX029, which showed the desired pharmacol. profile combining ERK1/2 inhibition with suppression of phospho-ERK1/2 (pERK) levels, and in addition, it possesses suitable preclin. pharmacokinetic properties predictive of once daily dosing in humans. ASTX029 is currently in a phase I-II clin. trial in patients with advanced solid tumors. In the experimental materials used by the author, we found 2,4-Dichloropyrimidine(cas: 3934-20-1Recommanded Product: 3934-20-1)

2,4-Dichloropyrimidine(cas: 3934-20-1) is a member of organic chlorides. Organic chlorides are compounds containing a carbon-chlorine bond, which are widely used in the oil field as a wax dissolver. They are generally not present in crude oils and are typically the result of additives, cleaning solutions or chemicals used for oil recovery.Recommanded Product: 3934-20-1

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

《Tuning nuclear receptor selectivity of Wy14,643 towards selective retinoid X receptor modulation》 was written by Pollinger, Julius; Gellrich, Leonie; Schierle, Simone; Kilu, Whitney; Schmidt, Jurema; Kalinowsky, Lena; Ohrndorf, Julia; Kaiser, Astrid; Heering, Jan; Proschak, Ewgenij; Merk, Daniel. Electric Literature of C4HCl3N2This research focused onWy14643 retinoid x receptor pharmacokinetics. The article conveys some information:

The fatty acid sensing nuclear receptor families retinoid X receptors (RXRs) and peroxisome proliferator-activated receptors (PPARs) hold therapeutic potential in neurodegeneration. Valuable pleiotropic activities of Wy14,643 (I) in models of such conditions exceed its known PPAR agonistic profile. Here, we characterize the compound as an RXR agonist explaining the pleiotropic effects and report its systematic structure-activity relationship anal. with the discovery of specific mol. determinants driving activity on PPARs and RXRs. We have designed close analogs of the drug comprising selective and dual agonism on RXRs and PPARs that may serve as superior pharmacol. tools to study the role and interplay of the nuclear receptors in various pathologies. A systematically optimized high potency RXR agonist (II) revealed activity in vivo and active concentrations in brain. With its lack of RXR/liver X receptor-mediated side effects and superior profile compared to classical rexinoids, it establishes a new class of innovative RXR modulators to overcome key challenges in RXR targeting drug discovery. The results came from multiple reactions, including the reaction of 2,4,6-Trichloropyrimidine(cas: 3764-01-0Electric Literature of C4HCl3N2)

2,4,6-Trichloropyrimidine(cas: 3764-01-0) is a member of organic chlorides. Organic chlorides are compounds containing a carbon-chlorine bond, which are widely used in the oil field as a wax dissolver. They are generally not present in crude oils and are typically the result of additives, cleaning solutions or chemicals used for oil recovery.Electric Literature of C4HCl3N2

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

SDS of cas: 519032-07-6On November 16, 2006 ,《4,5-Dihydroxypyrimidine Carboxamides and N-Alkyl-5-hydroxypyrimidinone Carboxamides Are Potent, Selective HIV Integrase Inhibitors with Good Pharmacokinetic Profiles in Preclinical Species》 appeared in Journal of Medicinal Chemistry. The author of the article were Summa, Vincenzo; Petrocchi, Alessia; Matassa, Victor G.; Gardelli, Cristina; Muraglia, Ester; Rowley, Michael; Paz, Odalys Gonzalez; Laufer, Ralph; Monteagudo, Edith; Pace, Paola. The article conveys some information:

The dihydroxypyrimidine carboxamide 4a was discovered as a potent and selective HIV integrase strand transfer inhibitor. The optimization of physicochem. properties, pharmacokinetic profiles, and potency led to the identification of (I) in the dihydroxypyrimidine series and (II) in the N-methylpyrimidinone series having low nanomolar activity in the cellular HIV spread assay in the presence of 50% normal human serum and very good pharmacokinetics in preclin. species. After reading the article, we found that the author used Methyl 2-benzyl-5,6-dihydroxypyrimidine-4-carboxylate(cas: 519032-07-6SDS of cas: 519032-07-6)

Methyl 2-benzyl-5,6-dihydroxypyrimidine-4-carboxylate(cas: 519032-07-6) belongs to pyrimidine. Pyrimidine derivatives also play an important role in drug development, either in concert with other compounds or on their own. SDS of cas: 519032-07-6They have been used in a wide variety of pharmaceuticals including general anesthetics, anti-epilepsy medication, anti-malaria medication, drugs for treating high blood pressure, and HIV medication.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

In 1966,Journal of Organic Chemistry included an article by Temple, Carroll Jr.; Montgomery, John A.. Formula: C6H7Cl2N3. The article was titled 《Some unusual reactions of 6-chloropurines with thioureas. 6-Alkylthiopurines and 2,2-diamino-2H-thiazolo[3,4,5-gh]purines from 2-(purin-6-yl)-2-thiopseudoureas》. The information in the text is summarized as follows:

Reaction of 6-chloropurine (I) with thiourea gave, in addition to purine-6(1H)-thione (II), 2,2-diamino-2H-thiazolo[3,4,5-gh]purine (III). 1-Ethyl-2-thiourea and I provided the corresponding ethyl derivative of III. From the reaction of 6-chloro-2-ethylpurine and thiourea in PrOH, 2-ethylpurine-6(1 H)-thione, 2,2-diamino-7-ethyl-2H-thiazolo[3,4,5-gh]purine, and 2-ethyl-6-(propylthio)purine (IV) were obtained, the formation of IV resulting from solvent participation. 6-Chloro-2,9-diethylpurine and thiourea in PrOH gave 2,9-diethyl-2-(propylthio)purine as a major component. Treatment of I, 2,6-dichloropurine, and 2-amino-6-chloropurine with 2-imidazolidinethione gave the corresponding 6-(2-imidazolinylthio)purine hydrochlorides (V, VI, and VII), resp. The free base of V and VI but not of VII appeared to form derivatives of III by intramol. addition Basic hydrolysis converted V to II, VI to 2-chlorohypoxanthine, and VII to thioguanine containing a trace of guanine. The results came from multiple reactions, including the reaction of 4,6-Dichloro-2-ethylpyrimidin-5-amine(cas: 6237-96-3Formula: C6H7Cl2N3)

4,6-Dichloro-2-ethylpyrimidin-5-amine(cas: 6237-96-3) belongs to anime. Nitrous acid converts secondary amines (aliphatic or aromatic) to N-nitroso compounds (nitrosamines): R2NH + HNO2 → R2N―NO. Some nitrosamines are potent cancer-inducing substances, and their possible formation is a serious consideration when nitrites, which are salts of nitrous acid, are present in foods or pharmaceutical preparations. Tertiary amines give rise to nitrosamines more slowly; an alkyl group is eliminated as an aldehyde or ketone, along with nitrous oxide, N2O.Formula: C6H7Cl2N3

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia