Month: October 2022

Electric Literature of C6H3Cl2N3In 2021 ,《Discovery of 6-[(3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2-methyl-3,4-dihydropyrimidin-4-one (IACS-15414), a Potent and Orally Bioavailable SHP2 Inhibitor》 appeared in Journal of Medicinal Chemistry. The author of the article were Czako, Barbara; Sun, Yuting; McAfoos, Timothy; Cross, Jason B.; Leonard, Paul G.; Burke, Jason P.; Carroll, Christopher L.; Feng, Ningping; Harris, Angela L.; Jiang, Yongying; Kang, Zhijun; Kovacs, Jeffrey J.; Mandal, Pijus; Meyers, Brooke A.; Mseeh, Faika; Parker, Connor A.; Yu, Simon S.; Williams, Christopher C.; Wu, Qi; Di Francesco, Maria Emilia; Draetta, Giulio; Heffernan, Timothy; Marszalek, Joseph. R.; Kohl, Nancy E.; Jones, Philip. The article conveys some information:

Src homol. 2 (SH2) domain-containing phosphatase 2 (SHP2) plays a role in receptor tyrosine kinase (RTK), neurofibromin-1 (NF-1), and Kirsten rat sarcoma virus (KRAS) mutant-driven cancers, as well as in RTK-mediated resistance, making the identification of small-mol. therapeutics that interfere with its function of high interest. Our quest to identify potent, orally bioavailable, and safe SHP2 inhibitors led to the discovery of a promising series of pyrazolopyrimidinones that displayed excellent potency but had a suboptimal in vivo pharmacokinetic (PK) profile. Hypothesis-driven scaffold optimization led us to a series of pyrazolopyrazines with excellent PK properties across species but a narrow human Ether-á-go-go-Related Gene (hERG) window. Subsequent optimization of properties led to the discovery of the pyrimidinone series, in which multiple members possessed excellent potency, optimal in vivo PK across species, and no off-target activities including no hERG liability up to 100μM. Importantly, compound 30 (IACS-15414) potently suppressed the mitogen-activated protein kinase (MAPK) pathway signaling and tumor growth in RTK-activated and KRASmut xenograft models in vivo. The results came from multiple reactions, including the reaction of 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine(cas: 90213-66-4Electric Literature of 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. Electric Literature of C6H3Cl2N3

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

COA of Formula: C4H2Cl2N2In 2019 ,《Discovery of a new class of valosine containing protein (VCP/P97) inhibitors for the treatment of non-small cell lung cancer》 appeared in Bioorganic & Medicinal Chemistry. The author of the article were Wang, Xueyuan; Bai, Enhe; Zhou, Hui; Sha, Sijia; Miao, Hang; Qin, Yanru; Liu, Zhaogang; Wang, Jia; Zhang, Haoyang; Lei, Meng; Liu, Jia; Hai, Ou; Zhu, Yongqiang. The article conveys some information:

Valosine containing protein (VCP/p97) is a member of the AAA ATPase family involved in several essential cellular functions and plays an important role in the ubiquitin-mediated degradation of misfolded proteins. P97 has a significant role in maintaining the cellular protein homeostasis for tumor cell growth and survival and has been found overexpressed in many tumor types. No new mol. entities based on p97 target were approved in clinic. Herein, a series of novel pyrimidine structures as p97 inhibitors were designed and synthesized. After enzymic evaluations, structure-activity relationships (SAR) were discussed in detailed. Among the screened compounds, derivative 35 showed excellent enzymic inhibitory activity (IC50, 36 nM). The cellular inhibition results showed that compound 35 had good antiproliferative activity against the non-small cell lung cancer A549 cells (IC50, 1.61 μM). Liver microsome stability showed that the half-life of compound 35 in human liver microsome was 42.3 min, which was more stable than the control CB-5083 (25.8 min). The in vivo pharmacokinetic results showed that the elimination phase half-lives of compound 35 were 4.57 h for ig and 3.64 h for iv, resp. and the oral bioavailability was only 4.5%. These results indicated that compound 35 could be effective for i.v. treatment of non-small cell lung cancer. In the experiment, the researchers used many compounds, for example, 2,4-Dichloropyrimidine(cas: 3934-20-1COA of Formula: C4H2Cl2N2)

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.COA of Formula: C4H2Cl2N2

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Application In Synthesis of 2,4-DichloropyrimidineIn 2021 ,《Discovery of N-(4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)-4-(4-methylpiperazin-1-yl)quinazolin-7-amine as a Novel, Potent, and Oral Cyclin-Dependent Kinase Inhibitor against Haematological Malignancies》 was published in Journal of Medicinal Chemistry. The article was written by Huang, Jianhang; Wang, Xinren; Dong, Ruinan; Liu, Xiaoyue; Li, Hongmei; Zhang, Tianyi; Xu, Junyu; Liu, Chenhe; Zhang, Yanmin; Hou, Shaohua; Tang, Weifang; Lu, Tao; Chen, Yadong. The article contains the following contents:

Hematol. malignancies (HM) start in blood forming tissue or in the cells of the immune system. Cyclin-dependent kinases (CDKs) regulate cell cycle progression, and some of them control cellular transcription. CDK inhibition can trigger apoptosis and could be particularly useful in hematol. malignancies. Herein, we describe our efforts toward the discovery of a novel series of quinazoline derivatives as CDK inhibitors. Intensive structural modifications lead to the identification of compound 37d as the most active inhibitors of CDKs 1, 2, 4, 8 and 9 with balancing potency and selectivity against CDKs. Further biol. studies revealed that compound 37d can arrest the cell cycle and induce apoptosis via activating PARP and caspase 3. More importantly, compound 37d showed good antitumor efficacy in multiple HM mice xenograft models with no obvious toxicity. These results indicated that CDK 1, 2, 4, 8, and 9 inhibitors could be potentially used to treat certain hematol. malignancies. 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. 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.Application In Synthesis of 2,4-Dichloropyrimidine

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

《A pyrrolo-pyrimidine derivative targets human primary AML stem cells in vivo》 was written by Saito, Yoriko; Yuki, Hitomi; Kuratani, Mitsuo; Hashizume, Yoshinobu; Takagi, Shinsuke; Honma, Teruki; Tanaka, Akiko; Shirouzu, Mikako; Mikuni, Junko; Handa, Noriko; Ogahara, Ikuko; Sone, Akiko; Najima, Yuho; Tomabechi, Yuri; Wakiyama, Motoaki; Uchida, Naoyuki; Tomizawa-Murasawa, Mariko; Kaneko, Akiko; Tanaka, Satoshi; Suzuki, Nahoko; Kajita, Hiroshi; Aoki, Yuki; Ohara, Osamu; Shultz, Leonard D.; Fukami, Takehiro; Goto, Toshio; Taniguchi, Shuichi; Yokoyama, Shigeyuki; Ishikawa, Fumihiko. Computed Properties of C23H22N4O And the article was included in Science Translational Medicine on April 17 ,2013. The article conveys some information:

Leukemia stem cells (LSCs) that survive conventional chemotherapy are thought to contribute to disease relapse, leading to poor long-term outcomes for patients with acute myeloid leukemia (AML). We previously identified a Src-family kinase (SFK) member, hematopoietic cell kinase (HCK), as a mol. target that is highly differentially expressed in human primary LSCs compared with human normal hematopoietic stem cells (HSCs). We performed a large-scale chem. library screen that integrated a high-throughput enzyme inhibition assay, in silico binding prediction, and crystal structure determination and found a candidate HCK inhibitor, RK-20449, a pyrrolo-pyrimidine derivative with an enzymic IC50 (half maximal inhibitory concentration) in the subnanomolar range. A crystal structure revealed that RK-20449 bound the activation pocket of HCK. In vivo administration of RK-20449 to nonobese diabetic (NOD)/severe combined immunodeficient (SCID)/IL2rgnull mice engrafted with highly aggressive therapy-resistant AML significantly reduced human LSC and non-stem AML burden. By eliminating chemotherapy-resistant LSCs, RK-20449 may help to prevent relapse and lead to improved patient outcomes in AML.7-Cyclopentyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(cas: 213743-31-8Computed Properties of C23H22N4O) was used in this study.

7-Cyclopentyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(cas: 213743-31-8) belongs to pyrimidine. Pyrimidine derivatives also play an important role in drug development, either in concert with other compounds or on their own. Computed Properties of C23H22N4OThey 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

《Tyrosine kinase inhibitor prodrug-loaded liposomes for controlled release at tumor microenvironment》 was written by Salmaso, Stefano; Mastrotto, Francesca; Roverso, Marco; Gandin, Valentina; De Martin, Sara; Gabbia, Daniela; De Franco, Michele; Vaccarin, Christian; Verona, Marco; Chilin, Adriana; Caliceti, Paolo; Bogialli, Sara; Marzaro, Giovanni. HPLC of Formula: 1193-21-1This research focused ontyrosine kinase inhibitor prodrug liposomes controlled release tumor microenvironment; Drug release; Kinase inhibitors; Liposomes; Microsomes; pH-dependent hydrolysis. The article conveys some information:

Tyrosine kinase inhibitors (TKIs) represent one of the most advanced class of therapeutics for cancer treatment. Most of them are also cytochrome P 450 (CYP) inhibitors and/or substrates thereof. Accordingly, their efficacy and/or toxicity can be affected by CYP-mediated metabolism and by metabolism-derived drug-drug interactions. In order to enhance the therapeutic performance of these drugs, we developed a prodrug (Pro962) of our TKI TK962 specifically designed for liposome loading and pH-controlled release in the tumor. A cholesterol moiety was linked to TK962 through pH-sensitive hydrazone bond for anchoring to the liposome phospholipid bilayer to prevent leakage of the prodrug from the nanocarrier. Bioactivity studies performed on isolated target kinases showed that the prodrug maintains only partial activity against them and the release of TK962 is required. Biopharmaceutical studies carried out with prodrug loaded liposomes showed that the prodrug was firmly associated with the vesicles and the drug release was prevented under blood-mimicking conditions. Conversely, conventional liposome loaded with TK962 readily released the drug. Flow cytometric studies showed that liposomes efficiently provided for intracellular prodrug delivery. The use of the hydrazone linker yielded a pH-controlled drug release, which resulted in about 50% drug release at pH 4 and 5 in 2 h. Prodrug, prodrug loaded liposomes and active lead compound have been tested against cancer cell lines in either 2D or 3D models. The liposome formulation showed higher cytotoxicity than the unformulated lead TK962 in both 2D and 3D models. The stability of prodrug, prodrug loaded liposomes and active lead compound in human serum and against human, mouse, and rat microsomes was also assessed, demonstrating that liposome formulations impair the metabolic reactions and protect the loaded compounds from catabolism. The results suggest that the liposomal formulation of pH releasable TKI prodrugs is a promising strategy to improve the metabolic stability, intracellular cancer cell delivery and release, and in turn the efficacy of this class of anticancer drugs. In the experiment, the researchers used 4,6-Dichloropyrimidine(cas: 1193-21-1HPLC of Formula: 1193-21-1)

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.HPLC of Formula: 1193-21-1

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Electric Literature of C23H22N4OOn September 1, 2015 ,《Discovery of thieno[3,2-c]pyridin-4-amines as novel Bruton’s tyrosine kinase (BTK) inhibitors》 was published in Bioorganic & Medicinal Chemistry. The article was written by Zhao, Xinge; Xin, Minhang; Wang, Yazhou; Huang, Wei; Jin, Qiu; Tang, Feng; Wu, Gang; Zhao, Yong; Xiang, Hua. The article contains the following contents:

A novel series of BTK inhibitors bearing thieno[3,2-c]pyridin-4-amine framework as the core scaffold were designed, synthesized and well characterized. In this paper, twenty one compounds displayed variant inhibitory activities against BTK in vitro, and compound 14g showed the most potent inhibitory activity against BTK enzyme, with the IC50 value of 12.8 nM. Moreover, compounds 14g displayed relatively good kinase selectivity and was subsequently evaluated in vivo for profiling its PK properties. This work identified the thieno[3,2-c]pyridin-4-amine derivatives as novel BTK inhibitors and verified the value of thieno[3,2-c]pyridin-4-amine scaffold in drug design. After reading the article, we found that the author used 7-Cyclopentyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(cas: 213743-31-8Electric Literature of C23H22N4O)

7-Cyclopentyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(cas: 213743-31-8) 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. Electric Literature of C23H22N4O

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Application of 29458-38-6On October 31, 1978 ,《O-Methylation of barbituric acids》 appeared in Farmaco, Edizione Scientifica. The author of the article were Stankiewicz, K.; Bobranski, B.. The article conveys some information:

Treating barbituric and N-phenylbarbituric acid with dry HCl in MeOH at room temperature gave 77.4% I (R = H) and 85% I (R = Ph), resp. In the part of experimental materials, we found many familiar compounds, such as 6-Methoxypyrimidine-2,4(1H,3H)-dione(cas: 29458-38-6Application of 29458-38-6)

6-Methoxypyrimidine-2,4(1H,3H)-dione(cas: 29458-38-6) 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.Application of 29458-38-6

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

COA of Formula: C13H12N2O4On November 12, 2009 ,《Coordination Chemistry Based Approach to Lipophilic Inhibitors of 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase》 appeared in Journal of Medicinal Chemistry. The author of the article were Deng, Lisheng; Sundriyal, Sandeep; Rubio, Valentina; Shi, Zheng-zheng; Song, Yongcheng. The article conveys some information:

1-Deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) in the non-mevalonate pathway found in most bacteria is a validated anti-infective drug target. Fosmidomycin, a potent DXR inhibitor, is active against Gram-neg. bacteria. A coordination chem. and structure based approach was used to discover a novel, lipophilic DXR inhibitor with an IC50 of 1.4 μM. It exhibited a broad spectrum of activity against Gram-neg. and -pos. bacteria with minimal inhibition concentrations of 20-100 μM (or 3.7-19 μg/mL). In the part of experimental materials, we found many familiar compounds, such as Methyl 2-benzyl-5,6-dihydroxypyrimidine-4-carboxylate(cas: 519032-07-6COA of Formula: C13H12N2O4)

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. COA of Formula: C13H12N2O4They 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

Quality Control of 3-(Pyrimidin-5-yl)benzaldehydeOn March 10, 2016, Wu, Yong-Jin; Guernon, Jason; Yang, Fukang; Snyder, Lawrence; Shi, Jianliang; McClure, Andrea; Rajamani, Ramkumar; Park, Hyunsoo; Ng, Alicia; Lewis, Hal; Chang, Chieh Ying; Camac, Dan; Toyn, Jeremy H.; Ahlijanian, Michael K.; Albright, Charles F.; Macor, John E.; Thompson, Lorin A. published an article in ACS Medicinal Chemistry Letters. The article was 《Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents》. The article mentions the following:

By targeting the flap backbone of the BACE1 active site, the authors discovered 6-dimethylisoxazole-substituted biaryl aminothiazine I with 34-fold improved BACE1 inhibitory activity over the lead compound The cocrystal structure of I bound to the active site indicated two hydrogen-bond interactions between the dimethylisoxazole and threonine 72 and glutamine 73 of the flap. Incorporation of the dimethylisoxazole substitution onto the related aminothiazine carboxamide series led to pyrazine-carboxamide II as a very potent BACE1 inhibitor (IC50 < 1 nM). This compound demonstrated robust brain Aβ reduction in rat dose-response studies. Thus, compound II may be useful in testing the amyloid hypothesis of Alzheimer's disease. The experimental process involved the reaction of 3-(Pyrimidin-5-yl)benzaldehyde(cas: 640769-70-6Quality Control of 3-(Pyrimidin-5-yl)benzaldehyde)

3-(Pyrimidin-5-yl)benzaldehyde(cas: 640769-70-6) 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. Quality Control of 3-(Pyrimidin-5-yl)benzaldehyde

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Wang, Yujie; Rong, Jie; Zhang, Bin; Hu, Liming; Wang, Xiaoli; Zeng, Chengchu published an article on February 15 ,2015. The article was titled 《Design and synthesis of N-methylpyrimidone derivatives as HIV-1 integrase inhibitors》, and you may find the article in Bioorganic & Medicinal Chemistry.Application In Synthesis of Methyl 2-benzyl-5,6-dihydroxypyrimidine-4-carboxylate The information in the text is summarized as follows:

A series of novel β-diketo derivatives which combined the virtues of dihydroxypyrimidine carboxamide derived from the evolution of diketo acids and polyhydroxylated aromatics moieties were designed and synthesized as potential HIV-1 integrase (IN) inhibitors and their inhibition to the strand transfer process of HIV-1 integrase and anti-HIV-1 activity evaluated. The result indicates that 3,4,5-trihydroxylated aromatic derivatives exhibit good inhibition to HIV-1 integrase, but dihydroxylated aromatic derivatives show little inhibition to HIV-1 integrase. In addition, the preliminary structure-activity relationship (SAR) of these new derivatives was rationalized by docking studies.Methyl 2-benzyl-5,6-dihydroxypyrimidine-4-carboxylate(cas: 519032-07-6Application In Synthesis of Methyl 2-benzyl-5,6-dihydroxypyrimidine-4-carboxylate) was used in this study.

Methyl 2-benzyl-5,6-dihydroxypyrimidine-4-carboxylate(cas: 519032-07-6) 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. Application In Synthesis of Methyl 2-benzyl-5,6-dihydroxypyrimidine-4-carboxylate

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia