Day: October 17, 2022

《Discovery of AB680: A Potent and Selective Inhibitor of CD73》 was published in Journal of Medicinal Chemistry in 2020. These research results belong to Lawson, Kenneth V.; Kalisiak, Jaroslaw; Lindsey, Erick A.; Newcomb, Eric T.; Leleti, Manmohan Reddy; Debien, Laurent; Rosen, Brandon R.; Miles, Dillon H.; Sharif, Ehesan U.; Jeffrey, Jenna L.; Tan, Joanne B. L.; Chen, Ada; Zhao, Sharon; Xu, Guifen; Fu, Lijuan; Jin, Lixia; Park, Tim W.; Berry, Wade; Moschutz, Susanne; Scaletti, Emma; Strater, Norbert; Walker, Nigel P.; Young, Stephen W.; Walters, Matthew J.; Schindler, Uli; Powers, Jay P.. COA of Formula: C6H3Cl2N3 The article mentions the following:

Extracellular adenosine (ADO), present in high concentrations in the tumor microenvironment (TME), suppresses immune function via inhibition of T cell and NK cell activation. Intratumoral generation of ADO depends on the sequential catabolism of ATP by two ecto-nucleotidases, CD39 (ATP → AMP) and CD73 (AMP → ADO). Inhibition of CD73 eliminates a major pathway of ADO production in the TME and can reverse ADO-mediated immune suppression. Extensive interrogation of structure-activity relationships (SARs), structure-based drug design, and optimization of pharmacokinetic properties culminated in the discovery of AB680, a highly potent (Ki = 5 pM), reversible, and selective inhibitor of CD73. AB680 is further characterized by very low clearance and long half-lives across preclin. species, resulting in a PK profile suitable for long-acting parenteral administration. AB680 is currently being evaluated in phase 1 clin. trials. Initial data show AB680 is well tolerated and exhibits a pharmacokinetic profile suitable for biweekly (Q2W) iv-administration in human. In the experiment, the researchers used many compounds, for example, 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine(cas: 90213-66-4COA of Formula: C6H3Cl2N3)

2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine(cas: 90213-66-4) belongs to pyrimidine. Pyrimidine nucleotide derivatives have a wide range of biological applications. For example, pyrimidine derivatives are useful in DNA repair studies involving cancer and epigenetics. COA of Formula: C6H3Cl2N3

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

《Process Development and Large-Scale Synthesis of BTK Inhibitor BIIB068》 was published in Organic Process Research & Development in 2020. These research results belong to Li, Chaomin; Franklin, Lloyd; Chen, Robbie; Mack, Tamera; Humora, Michael; Ma, Bin; Hopkins, Brian T.; Guzowski, John; Zheng, Fengmei; MacPhee, Michael; Lin, Yiqing; Ferguson, Steven; Patience, Daniel; Moniz, George A.; Kiesman, William F.; O’Brien, Erin M.. Computed Properties of C4H2Cl2N2 The article mentions the following:

Chem. process development efforts leading to multi-kilogram production of BIIB068 hemi-adipate was discussed. Process optimization has resulted in (1) removal of late transition metal from the process; (2) streamlined process with significantly improved overall yield; (3) appropriate impurity control (including potential mutagenic impurities or PMI) which enabled delivery of quality material for toxicol. studies and clin. trials. In the experiment, the researchers used many compounds, for example, 2,4-Dichloropyrimidine(cas: 3934-20-1Computed Properties of C4H2Cl2N2)

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.Computed Properties of C4H2Cl2N2

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

《General dual functionalisation of biomacromolecules via a cysteine bridging strategy》 was written by Walsh, Stephen J.; Iegre, Jessica; Seki, Hikaru; Bargh, Jonathan D.; Sore, Hannah F.; Parker, Jeremy S.; Carroll, Jason S.; Spring, David R.. COA of Formula: C4HCl3N2 And the article was included in Organic & Biomolecular Chemistry in 2020. The article conveys some information:

Site-selective modification of peptides and proteins resulted in the development of a host of novel tools for the study of cellular systems or the synthesis of enhanced biotherapeutics. There is a need for useful methodologies that enable site-selective modification of native peptides or proteins, which is even more prevalent when modification of the biomol. with multiple payloads is desired. Herein, the authors report the development of a novel dual functional divinylpyrimidine (dfDVP) platform that enables robust and modular modification of peptides, antibody fragments and antibodies. These biomacromols. could be easily functionalized with a range of functional payloads (e.g. fluorescent dyes, cytotoxic warheads or cell-penetrating tags). Importantly, the dual functionalized peptides and antibodies demonstrated exquisite bioactivity in a range of in vitro cellular assays, showcasing the enhanced utility of these bioactive conjugates. In the experiment, the researchers used many compounds, for example, 2,4,6-Trichloropyrimidine(cas: 3764-01-0COA of Formula: C4HCl3N2)

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.COA of Formula: C4HCl3N2

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

《Indazolyl-substituted piperidin-4-yl-aminopyrimidines as HIV-1 NNRTIs: Design, synthesis and biological activities》 was written by Xiao, Ting; Tang, Jia-Fan; Meng, Ge; Pannecouque, Christophe; Zhu, Yuan-Yuan; Liu, Gen-Yan; Xu, Zhi-Qiang; Wu, Feng-Shou; Gu, Shuang-Xi; Chen, Fen-Er. Recommanded Product: 3934-20-1 And the article was included in European Journal of Medicinal Chemistry in 2020. The article conveys some information:

A series of indazolyl-substituted piperidin-4-yl-aminopyrimidines (IPAPYs) I (R = 2-Cl, 2-Br, 2-CF3, etc.) were designed from two potent HIV-1 NNRTIs piperidin-4-yl-aminopyrimidine and diaryl ether as the lead compounds by mol. hybridization strategy. The target mols. I were synthesized and evaluated for their anti-HIV activities and cytotoxicities in MT-4 cells. I displayed moderate to excellent activities against wild-type (WT) HIV-1 with EC50 values ranging from 1.5 to 0.0064μM. Among them, I (R = 2,6-diMe-4-CN) was regarded as the most excellent compound against WT HIV-1 (EC50 = 6.4 nM, SI = 2500). And also, it displayed potent activities against K103 N (EC50 = 0.077μM), Y181C (EC50 = 0.11μM), E138K (EC50 = 0.057μM), and moderate activity against double mutants RES056 (EC50 = 8.7μM). Moreover, the structure-activity relationships (SARs) were summarized, and the mol. docking was performed to investigate the binding mode of IPAPYs and HIV-1 reverse transcriptase. 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 chloride content in crude oil can be detected through specialized laboratory analysis. Care and attention are essential while sampling and testing.Recommanded Product: 3934-20-1

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Van de Poel, Amanda; Toledo-Sherman, Leticia; Breccia, Perla; Cachope, Roger; Bate, Jennifer R.; Angulo-Herrera, Ivan; Wishart, Grant; Matthews, Kim L.; Martin, Sarah L.; Peacock, Marcus; Barnard, Amy; Cox, Helen C.; Jones, Graham; McAllister, George; Vater, Huw; Esmieu, William; Clissold, Cole; Lamers, Marieke; Leonard, Philip; Jarvis, Rebecca E.; Blackaby, Wesley; Eznarriaga, Maria; Lazari, Ovadia; Yates, Dawn; Rose, Mark; Jang, Sung-Wook; Munoz-Sanjuan, Ignacio; Dominguez, Celia published their research in Journal of Medicinal Chemistry in 2021. The article was titled 《Structure-Based Exploration of Selectivity for ATM Inhibitors in Huntington’s Disease》.Safety of 2,4,6-Trichloropyrimidine The article contains the following contents:

Our group has recently shown that brain-penetrant ataxia telangiectasia-mutated (ATM) kinase inhibitors may have potential as novel therapeutics for the treatment of Huntington’s disease (HD). However, the previously described pyranone-thioxanthenes (e.g., 4) failed to afford selectivity over a vacuolar protein sorting 34 (Vps34) kinase, an important kinase involved with autophagy. Given that impaired autophagy has been proposed as a pathogenic mechanism of neurodegenerative diseases such as HD, achieving selectivity over Vps34 became an important objective for our program. Here, we report the successful selectivity optimization of ATM over Vps34 by using X-ray crystal structures of a Vps34-ATM protein chimera where the Vps34 ATP-binding site was mutated to approx. that of an ATM kinase. The morpholino-pyridone and morpholino-pyrimidinone series that resulted as a consequence of this selectivity optimization process have high ATM potency and good oral bioavailability and have lower mol. weight, reduced lipophilicity, higher aqueous solubility, and greater synthetic tractability compared to the pyranone-thioxanthenes. In addition to this study using 2,4,6-Trichloropyrimidine, there are many other studies that have used 2,4,6-Trichloropyrimidine(cas: 3764-01-0Safety of 2,4,6-Trichloropyrimidine) was used in this study.

2,4,6-Trichloropyrimidine(cas: 3764-01-0) 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.Safety of 2,4,6-Trichloropyrimidine

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Taylor, Connor J.; Seki, Hikaru; Dannheim, Friederike M.; Willis, Mark J.; Clemens, Graeme; Taylor, Brian A.; Chamberlain, Thomas W.; Bourne, Richard A. published their research in Reaction Chemistry & Engineering in 2021. The article was titled 《An automated computational approach to kinetic model discrimination and parameter estimation》.Application of 3764-01-0 The article contains the following contents:

We herein report exptl. applications of a novel, automated computational approach to chem. reaction network (CRN) identification. This report shows the first chem. applications of an autonomous tool to identify the kinetic model and parameters of a process, when considering both catalytic species and various integer and non-integer orders in the model′s rate laws. This kinetic anal. methodol. requires only the input of the species within the chem. system (starting materials, intermediates, products, etc.) and corresponding time-series concentration data to determine the kinetic information of the chem. of interest. This is performed with minimal human interaction and several case studies were performed to show the wide scope and applicability of this process development tool. The approach described herein can be employed using exptl. data from any source and the code for this methodol. is also provided open-source. In the experimental materials used by the author, we found 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. Almost all organochlorine compounds are synthesized. It is widely used as intermediates, solvents and pesticides of chemical synthetic products.Application of 3764-01-0

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Al-Khawaldeh, Islam; Al Yasiri, Mohammed J.; Aldred, Gregory G.; Basmadjian, Christine; Bordoni, Cinzia; Harnor, Suzannah J.; Heptinstall, Amy B.; Hobson, Stephen J.; Jennings, Claire E.; Khalifa, Shaimaa; Lebraud, Honorine; Martin, Mathew P.; Miller, Duncan C.; Shrives, Harry J.; de Souza, Joao V.; Stewart, Hannah L.; Temple, Max; Thomas, Huw D.; Totobenazara, Jane; Tucker, Julie A.; Tudhope, Susan J.; Wang, Lan Z.; Bronowska, Agnieszka K.; Cano, Celine; Endicott, Jane A.; Golding, Bernard T.; Hardcastle, Ian R.; Hickson, Ian; Wedge, Stephen R.; Willmore, Elaine; Noble, Martin E. M.; Waring, Michael J. published their research in Journal of Medicinal Chemistry in 2021. The article was titled 《An Alkynylpyrimidine-Based Covalent Inhibitor That Targets a Unique Cysteine in NF-κB-Inducing Kinase》.Computed Properties of C4H2Cl2N2 The article contains the following contents:

NF-κB-inducing kinase (NIK) is a key enzyme in the noncanonical NF-κB pathway, of interest in the treatment of a variety of diseases including cancer. Validation of NIK as a drug target requires potent and selective inhibitors. The protein contains a cysteine residue at position 444 in the back pocket of the active site, unique within the kinome. Anal. of existing inhibitor scaffolds and early structure-activity relationships (SARs) led to the design of C444-targeting covalent inhibitors based on alkynyl heterocycle warheads. Mass spectrometry provided proof of the covalent mechanism, and the SAR was rationalized by computational modeling. Profiling of more potent analogs in tumor cell lines with constitutively activated NIK signaling induced a weak antiproliferative effect, suggesting that kinase inhibition may have limited impact on cancer cell growth. This study shows that alkynyl heterocycles are potential cysteine traps, which may be employed where common Michael acceptors, such as acrylamides, are not tolerated. In the experiment, the researchers used many compounds, for example, 2,4-Dichloropyrimidine(cas: 3934-20-1Computed Properties of C4H2Cl2N2)

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.Computed Properties of C4H2Cl2N2

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Kamaura, Masahiro; Kubo, Osamu; Sugimoto, Hiromichi; Noguchi, Naoyoshi; Miyashita, Hirohisa; Abe, Shinichi; Matsuda, Kae; Tsujihata, Yoshiyuki; Odani, Tomoyuki; Iwasaki, Shinji; Murata, Toshiki; Sato, Kenjiro published an article in 2021. The article was titled 《Discovery of a novel series of indolinylpyrimidine-based GPR119 agonists: Elimination of ether-a-go-go-related gene liability using a hydrogen bond acceptor-focused approach》, and you may find the article in Bioorganic & Medicinal Chemistry.Product Details of 1193-21-1 The information in the text is summarized as follows:

We previously identified a novel series of indolinylpyrimidine derivatives exemplified by 2 in Figure 1, which is an indoline based derivative, as potent GPR119 agonists. Despite the attractive potency of 2, this compound inhibited the human ether-a-go-go-related gene (hERG) K+ channel. We elucidated crucial roles of the methylsulfonyl group of 2 in its interaction with the hERG channel and the GPR119 receptor, presumably as a hydrogen bond acceptor (HBA). To remove the undesirable hERG inhibitory activity, a strategy was implemented to arrange an HBA on a less conformationally flexible framework at the indoline 5-position instead of the methylsulfonyl group. This successfully led to the discovery of a piperidinone ring as a desirable motif at the indoline 5-position, which could minimize hERG liability as shown by 24b. Further optimization focused on the reduction of lipophilicity in terms of more favorable drug-like properties. Consequently, the introduction of a hydroxy group at the 3-position of the piperidinone ring effectively reduced lipophilicity without compromising GPR119 potency, resulting in the identification of (3S)-3-hydroxy-1-{1-[6-({1-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}oxy)pyrimidin-4-yl]- 2,3-dihydro-1H-indol-5-yl}piperidin-2-one ((S)-29) as a novel, potent, and orally bioavailable GPR119 agonist with a well-balanced profile. The pharmacol. effects of this compound were also confirmed after single and chronic oral administration in diabetic animal models. In the experiment, the researchers used 4,6-Dichloropyrimidine(cas: 1193-21-1Product Details of 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.Product Details of 1193-21-1

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

In 2022,Fairhurst, Robin A.; Furet, Pascal; Imbach-Weese, Patricia; Stauffer, Frederic; Rueeger, Heinrich; McCarthy, Clive; Ripoche, Sebastien; Oswald, Susanne; Arnaud, Bertrand; Jary, Aline; Maira, Michel; Schnell, Christian; Guthy, Daniel A.; Wartmann, Markus; Kiffe, Michael; Desrayaud, Sandrine; Blasco, Francesca; Widmer, Toni; Seiler, Frank; Gutmann, Sascha; Knapp, Mark; Caravatti, Giorgio published an article in Journal of Medicinal Chemistry. The title of the article was 《Identification of NVP-CLR457 as an Orally Bioavailable Non-CNS-Penetrant pan-Class IA Phosphoinositol-3-Kinase Inhibitor》.Quality Control of 2,4,6-Trichloropyrimidine The author mentioned the following in the article:

Balanced pan-class I phosphoinositide 3-kinase inhibition as an approach to cancer treatment offers the prospect of treating a broad range of tumor types and/or a way to achieve greater efficacy with a single inhibitor. Taking buparlisib as the starting point, the balanced pan-class I PI3K inhibitor 40 (NVP-CLR457) was identified with what was considered to be a best-in-class profile. Key to the optimization to achieve this profile was eliminating a microtubule stabilizing off-target activity, balancing the pan-class I PI3K inhibition profile, minimizing CNS penetration, and developing an amorphous solid dispersion formulation. A rationale for the poor tolerability profile of 40 in a clin. study is discussed. The experimental process involved the reaction of 2,4,6-Trichloropyrimidine(cas: 3764-01-0Quality Control of 2,4,6-Trichloropyrimidine)

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.Quality Control of 2,4,6-Trichloropyrimidine

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Recommanded Product: 1193-21-1In 2021 ,《Design, synthesis, and structure-activity relationships study of N-pyrimidyl/pyridyl-2-thiazolamine analogues as novel positive allosteric modulators of M3 muscarinic acetylcholine receptor》 appeared in Chemical & Pharmaceutical Bulletin. The author of the article were Tanaka, Hiroaki; Akaiwa, Michinori; Negoro, Kenji; Kawaminami, Eiji; Mihara, Hisashi; Fuji, Hideyoshi; Okimoto, Risa; Ino, Katsutoshi; Ishizu, Kenichiro; Takahashi, Taisuke. The article conveys some information:

The M3 muscarinic acetylcholine receptor (mAChR) plays an essential pharmacol. role in mediating a broad range of actions of acetylcholine (ACh) released throughout the periphery and central nerve system (CNS). Nevertheless, its agonistic functions remain unclear due to the lack of available subtype-selective agonists or pos. allosteric modulators (PAMs). Based on the extended structure-activity relationships (SARs) study on a previously reported PAM of the M3 mAChR, 2-acylaminothiazole I, aa series of N-azinyl-2-thiazolamine analogs II (X = pyridine-2,6-diyl, pyrimidine-2,4-diyl, 5-fluoropyrimidine-4,6-diyl, pyrazine-3,6-diyl, etc.) were identified as new scaffolds. The SARs study was rationalized using conformational analyses based on intramol. interactions. A comprehensive study of a series of analogs described in this paper suggests that a unique sulfur-nitrogen nonbonding interaction in the N-azinyl-2-thiazolamine moiety enables conformations that are essential for activity. Further, a SARs study around the N-pyrimidyl/pyridyl-2-thiazolamine core culminated in the discovery of the compound II (X = 5-fluoro-2-methylpyrimidine-4,6-diyl), which showed potent in vitro PAM activity for the M3 mAChR with excellent subtype selectivity. Compound II (X = 5-fluoro-2-methylpyrimidine-4,6-diyl) also showed a distinct pharmacol. effect on isolated smooth muscle tissue from rat bladder and favorable pharmacokinetics profiles, suggesting its potential as a chem. tool for probing the M3 mAChR in further research. In addition to this study using 4,6-Dichloropyrimidine, there are many other studies that have used 4,6-Dichloropyrimidine(cas: 1193-21-1Recommanded Product: 1193-21-1) was used in this study.

4,6-Dichloropyrimidine(cas: 1193-21-1) 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: 1193-21-1

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia