Month: October 2022

Norman, Mark H.; Zhu, Jiawang; Fotsch, Christopher; Bo, Yunxin; Chen, Ning; Chakrabarti, Partha; Doherty, Elizabeth M.; Gavva, Narender R.; Nishimura, Nobuko; Nixey, Thomas; Ognyanov, Vassil I.; Rzasa, Robert M.; Stec, Markian; Surapaneni, Sekhar; Tamir, Rami; Viswanadhan, Vellarkad N.; Treanor, James J. S. published an article in Journal of Medicinal Chemistry. The title of the article was 《Novel Vanilloid Receptor-1 Antagonists: 1. Conformationally Restricted Analogues of trans-Cinnamides》.Computed Properties of C11H6ClF3N2 The author mentioned the following in the article:

The vanilloid receptor-1 (VR1 or TRPV1) is a member of the transient receptor potential (TRP) family of ion channels and plays a role as an integrator of multiple pain-producing stimuli. From a high-throughput screening assay, measuring calcium uptake in TRPV1-expressing cells, we identified an N-aryl trans-cinnamide (AMG9810, compound 9) that acts as a potent TRPV1 antagonist. We have demonstrated the antihyperalgesic properties of 9 in vivo and have also reported the discovery of novel, orally bioavailable cinnamides derived from this lead. Herein, we expand our investigations and describe the synthesis and biol. evaluation of a series of conformationally constrained analogs of the s-cis conformer of compound 9. These investigations resulted in the identification of 4-amino- and 4-oxopyrimidine cores as suitable isosteric replacements for the trans-acrylamide moiety. The best examples from this series, pyrimidines 79 and 74 (I), were orally bioavailable and exhibited potent antagonism of both rat (IC50 = 4.5 and 0.6 nM, resp.) and human TRPV1 (IC50 = 7.4 and 3.7 nM, resp.). In addition, compound 74 was shown to be efficacious at blocking a TRPV1-mediated physiol. response in vivo in the capsaicin-induced hypothermia model in rats; however, it was ineffective at preventing thermal hyperalgesia induced by complete Freund’s adjuvant in rats. The experimental part of the paper was very detailed, including the reaction process of 4-Chloro-6-(4-(trifluoromethyl)phenyl)pyrimidine(cas: 659729-09-6Computed Properties of C11H6ClF3N2)

4-Chloro-6-(4-(trifluoromethyl)phenyl)pyrimidine(cas: 659729-09-6) 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. Computed Properties of C11H6ClF3N2

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

The author of 《Inhibition of Lipid Signaling Enzyme Diacylglycerol Kinase ε Attenuates Mutant Huntingtin Toxicity》 were Zhang, Ningzhe; Li, Bensheng; Al-Ramahi, Ismael; Cong, Xin; Held, Jason M.; Kim, Eugene; Botas, Juan; Gibson, Bradford W.; Ellerby, Lisa M.. And the article was published in Journal of Biological Chemistry in 2012. Application of 213743-31-8 The author mentioned the following in the article:

Huntington’s disease (HD) is a dominantly inherited neurodegenerative disease caused by a polyglutamine expansion in the protein huntingtin (Htt). Striatal and cortical neuronal loss are prominent features of this disease. No disease-modifying treatments have been discovered for HD. To identify new therapeutic targets in HD, we screened a kinase inhibitor library for mols. that block mutant Htt cellular toxicity in a mouse HD striatal cell model, Hdh111Q/111Q cells. We found that diacylglycerol kinase (DGK) inhibitor II (R59949) decreased caspase-3/7 activity after serum withdrawal in striatal Hdh111Q/111Q cells. In addition, R59949 decreased the accumulation of a 513-amino acid N-terminal Htt fragment processed by caspase-3 and blocked alterations in lipid metabolism during serum withdrawal. To identify the diacylglycerol kinase mediating this effect, we knocked down all four DGK isoforms expressed in the brain (β, γ, ε, and ζ) using siRNA. Only the knockdown of the family member, DGKε, blocked striatal Hdh111Q/111Q-mediated toxicity. We also investigated the significance of these findings in vivo. First, we found that reduced function of the Drosophila DGKε homolog significantly improves Htt-induced motor dysfunction in a fly model of HD. In addition, we find that the levels of DGKε are increased in the striatum of R6/2 HD transgenic mice when compared with littermate controls. Together, these findings indicate that increased levels of kinase DGKε contribute to HD pathogenesis and suggest that reducing its levels or activity is a potential therapy for HD. In the experiment, the researchers used 7-Cyclopentyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(cas: 213743-31-8Application of 213743-31-8)

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

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Brakta, Mohamed; Daves, G. Doyle Jr. published their research in Journal of the Chemical Society on August 7 ,1992. The article was titled 《Efficient synthesis of 3H,5H-pyrrolo[3,2-d]pyrimidin-4-one》.Computed Properties of C5H4ClN3O3 The article contains the following contents:

Palladium-catalyzed cross-coupling of 4-iodo-6-methoxy-5-nitropyrmidine and trimethyl(tributylstannylethynyl)silane to form the corresponding 4-(trimethylsilylethynyl)pyrimidine I and subsequent construction of an annellated pyrrolo ring II provides an efficient route to the title pyrrolo[3,2-d]pyrimidine system III. In the experiment, the researchers used many compounds, for example, 4-Chloro-6-methoxy-5-nitropyrimidine(cas: 52854-14-5Computed Properties of C5H4ClN3O3)

4-Chloro-6-methoxy-5-nitropyrimidine(cas: 52854-14-5) 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.Computed Properties of C5H4ClN3O3

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

In 1988,Saxena, Naveen K.; Hagenow, Brenda M.; Genzlinger, Gail; Turk, Steven R.; Drach, John C.; Townsend, Leroy B. published 《Synthesis and antiviral activity of certain 4-substituted and 2,4-disubstituted 7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidines》.Journal of Medicinal Chemistry published the findings.Product Details of 90213-66-4 The information in the text is summarized as follows:

Alkylation of the Na salt of pyrimidine I (R = MeS, R1 = H) with AcOCH2CH2OCH2Br gave I (R = MeS, R1 = AcOCH2CH2OCH2) which was converted into the title pyrimidines II (R = MeS, R2 = Cl, NH2; R = H, OH, MeSO2, MeO, R2 = NH2). Similarly, I (R = Cl, NHAc, R1 = H) were alkylated and further transformed into II (R = Cl, R2 = Cl, NH2; R = NHAc, R2 = Cl; R = R2 = NH2). In tests of II involving human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1), only slight activity and cytotoxicity were observed The most active compounds I(R = Cl, R1 = AcOCH2CH2OCH2) and II (R = R2 = Cl), were slightly more active against HCMV than acyclovir, but both compounds were inactive against HSV-1. The activity against HCMV, however, was not well separated from cytotoxicity leading to the conclusion that these compounds did not merit further study. In the experimental materials used by the author, we found 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine(cas: 90213-66-4Product Details of 90213-66-4)

2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine(cas: 90213-66-4) belongs to pyrimidine. Pyrimidine derivatives also play an important role in drug development, either in concert with other compounds or on their own. Product Details of 90213-66-4They 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 2017,Li, Wenlu; Sun, Qinsheng; Song, Lu; Gao, Chunmei; Liu, Feng; Chen, Yuzong; Jiang, Yuyang published 《Discovery of 1-(3-aryl-4-chlorophenyl)-3-(p-aryl)urea derivatives against breast cancer by inhibiting PI3K/Akt/mTOR and Hedgehog signalings》.European Journal of Medicinal Chemistry published the findings.Name: 2,4,6-Trichloropyrimidine The information in the text is summarized as follows:

PI3K/Akt/mTOR and hedgehog (Hh) signalings are two important pathways in breast cancer, which are usually connected with the drug resistance and cancer migration. Many studies indicated that PI3K/Akt/mTOR inhibitors and Hh inhibitors displayed synergistic effects, and the combination of the two signaling drugs could delay drug resistance and inhibit cancer migration in breast cancer. Therefore, the development of mols. simultaneously inhibiting these two pathways is urgent needed. Based on the structures of PI3K inhibitor buparlisib and Hh inhibitor vismodegib, a series of hybrid structures were designed and synthesized utilizing rational drug design and computer-based drug design. Several compounds displayed excellent antiproliferative activities against several breast cancer cell lines, including triple-neg. breast cancer (TNBC) MDA-MB-231 cell. Further mechanistic studies demonstrated that the representative compound 9i could inhibit both PI3K/Akt/mTOR and hedgehog (Hh) signalings by inhibiting the phosphorylation of S6K and Akt as well as decreasing the SAG elevated expression of Gli1. Compound 9i could also induce apoptosis remarkably in T47D and MDA-MB-231 cells. In the transwell assay, 9i showed significant inhibition on the migration of MDA-MB-231. After reading the article, we found that the author used 2,4,6-Trichloropyrimidine(cas: 3764-01-0Name: 2,4,6-Trichloropyrimidine)

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.Name: 2,4,6-Trichloropyrimidine

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

In 2017,Xie, Hui; Zeng, Shaogao; He, Yuwen; Zhang, Guicheng; Yu, Pengjiu; Zhong, Guifa; Xu, Hongjiang; Yang, Ling; Wang, Shanchun; Zhao, Xin; Hu, Wenhui published 《Rapid generation of a novel DPP-4 inhibitor with long-acting properties: SAR study and PK/PD evaluation》.European Journal of Medicinal Chemistry published the findings.Related Products of 90213-66-4 The information in the text is summarized as follows:

Drug compliance is critical for patients with chronic diseases such as diabetes. In our continuous effort to find better glucose-lowering agents, an exploration for long-acting DPP-4 inhibitors had been launched. Based on our previously reported compounds bearing a pyrrolopyrimidine scaffold, the lead compound 4a (IC50 = 2.3 nM, t1/2(rat) = 5.46 h) with pharmacokinetic superiority was rapidly determined Further SAR study indicated that the pyrrole ring was generally tolerable for variation, in which a β-substitution gave a better DPP-4 affinity. In depth evaluation of the pyrrole ring β position identified a highly potent compound 12a (IC50 = 0.76 nM, t1/2(rat) = 7.89 h). In vivo pharmacodynamics tests demonstrated similar or even slightly better sustained DPP-4 inhibition for compounds 4a and 12a compared with the first marketed once-weekly drug trelagliptin in this category, indicating that improvements to DPP-4 inhibitory activity or pharmacokinetic profile might be feasible ways to rapidly generate long-acting DPP-4 inhibitors. The experimental process involved the reaction of 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine(cas: 90213-66-4Related Products of 90213-66-4)

2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine(cas: 90213-66-4) belongs to pyrimidine. Pyrimidine derivatives also play an important role in drug development, either in concert with other compounds or on their own. Related Products of 90213-66-4They 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 2017,Thorarensen, Atli; Dowty, Martin E.; Banker, Mary Ellen; Juba, Brian; Jussif, Jason; Lin, Tsung; Vincent, Fabien; Czerwinski, Robert M.; Casimiro-Garcia, Agustin; Unwalla, Ray; Trujillo, John I.; Liang, Sidney; Balbo, Paul; Che, Ye; Gilbert, Adam M.; Brown, Matthew F.; Hayward, Matthew; Montgomery, Justin; Leung, Louis; Yang, Xin; Soucy, Sarah; Hegen, Martin; Coe, Jotham; Langille, Jonathan; Vajdos, Felix; Chrencik, Jill; Telliez, Jean-Baptiste published 《Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (PF-06651600) Allowing for the Interrogation of JAK3 Signaling in Humans》.Journal of Medicinal Chemistry published the findings.Synthetic Route of C6H3Cl2N3 The information in the text is summarized as follows:

Significant work has been dedicated to the discovery of JAK kinase inhibitors resulting in several compounds entering clin. development and two FDA approved NMEs. However, despite significant effort during the past two decades, identification of highly selective JAK3 inhibitors has eluded the scientific community. A significant effort within the research organization has resulted in the identification of the first orally active JAK3 specific inhibitor, which achieves JAK isoform specificity through covalent interaction with a unique JAK3 residue Cys-909. The relatively rapid resynthesis rate of the JAK3 enzyme presented a unique challenge in the design of covalent inhibitors with appropriate pharmacodynamics properties coupled with limited unwanted off-target reactivity. This effort resulted in the identification of PF-06651600 I, a potent and low clearance compound with demonstrated in vivo efficacy. The favorable efficacy and safety profile of this specific JAK3 inhibitor I led to its evaluation in several human clin. studies. In the experiment, the researchers used 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine(cas: 90213-66-4Synthetic Route 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. Synthetic Route of C6H3Cl2N3

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

The author of 《Early Process Development of an Irreversible Epidermal Growth Factor Receptor (EGFR) T790 M Inhibitor》 were Tao, Yong; Keene, Nandell F.; Wiglesworth, Kristin E.; Sitter, Barbara; McWilliams, J. Christopher. And the article was published in Organic Process Research & Development in 2019. Electric Literature of C6H3Cl2N3 The author mentioned the following in the article:

The original synthesis of the irreversible epidermal growth factor receptor (EGFR) T790 M inhibitor 1 (I) was enabled by successful application of ammonium hydroxide to cleanly cleave the N-hydroxymethyl group and by development of high yielding conditions for the subsequent amidation reaction. Furthermore, a protection-free and regioselective new synthetic route was developed that shortened the synthesis from the original 8 steps to 6 steps and improved the overall yield from 5% to 34% on scale. Crystallizations of 1 and intermediates were correspondingly developed to control the quality en route. After reading the article, we found that the author used 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 derivatives also play an important role in drug development, either in concert with other compounds or on their own. Electric Literature of C6H3Cl2N3They 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

The author of 《Process Development and Scale Up of a Selective JAK3 Covalent Inhibitor PF-06651600》 were Tao, Yong; McWilliams, J. Christopher; Wiglesworth, Kristin E.; Girard, Kevin P.; Makowski, Teresa M.; Sach, Neal W.; Mustakis, Jason G.; Mehta, Ruchi; Trujillo, John I.; Chen, Xiaofeng; Li, Tangqing; Shi, Feng; Xie, Chengfu; Zhang, Qing. And the article was published in Organic Process Research & Development in 2019. Safety of 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine The author mentioned the following in the article:

A scalable process for PF-06651600 was developed through successful enabling of the first generation synthesis. The synthesis highlights include the following: (1) replacement of costly PtO2 with a less expensive 5% Rh/C catalyst for a pyridine hydrogenation, (2) identification of a diasteromeric salt crystallization to isolate the enantiomerically pure cis-isomer directly from a racemic mixture of cis/trans isomers, (3) a high yielding amidation via Schotten-Baumann conditions, and (4) critical development of a reproducible crystallization procedure for a stable crystalline salt 1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one p-Toluenesulfonate, which is suitable for long-term storage and tablet formulation. All chromatog. purifications, including two chiral SFC chromatog. separations, were eliminated. Combined with other improvements in each step of the synthesis, the overall yield was increased from 5% to 14%. Several multikilogram batches of the API were delivered to support clin. studies. In the experiment, the researchers used 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine(cas: 90213-66-4Safety of 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine)

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. Safety of 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

《Design, synthesis, and anticancer evaluation of acetamide and hydrazine analogues of pyrimidine》 was published in Journal of Heterocyclic Chemistry in 2020. These research results belong to Khazir, Jabeena; Mir, Bilal Ahmad; Chashoo, Gousia; Maqbool, Tariq; Riley, Darren; Pilcher, Lynne. Product Details of 1193-21-1 The article mentions the following:

A library of acetamide I [R = 2-hydroxyethylamino, 1-pyrrolidinyl, N-morpholinyl, etc.] and hydrazine II [R1 = 1-pyrrolidinyl, 1-piperidinyl, N-morpholinyl, 4-propanoyl-1-piperidyl; R2 = H, 2-Br, 3,4-di-MeO, etc.] analogs were generated on the pyrimidine ring through a multistep reaction starting from 5-nitro-pyrimidine-4,6-diol and pyrimidine-4,6-diol, resp. The synthesized analogs I and II were screened for in-vitro cytotoxic activity against various human cancer cell lines like HCT-1 and HT-15 (colon), MCF-7(breast), PC-3 (prostrate), SF268 (CNS) using MTT method. From the bioassay results, it was observed that even though many of the synthesized derivatives I and II exhibited a good potency against various screened cancer cell lines, compound I [R = 1-piperidinyl] showed potent anticancer activity on all the tested cancer cell lines with IC50 value of 0.36μM on CNS cell line and 1.6μM on HT-21 cell line, and compound II [R1 = N-morpholinyl, R2 = 2-OH] showed potent activity against three tested cancer cell lines with IC50 value of 0.76μM on HT-29 cell line, 2.6μM on HCT-15 and 3.2μM on MCF-7 cell line. After reading the article, we found that the author 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. Almost all organochlorine compounds are synthesized. It is widely used as intermediates, solvents and pesticides of chemical synthetic products.Product Details of 1193-21-1

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia