13514-79-9Relevant articles and documents
Superior Pyrimidine Derivatives as Selective ABCG2 Inhibitors and Broad-Spectrum ABCB1, ABCC1, and ABCG2 Antagonists
Silbermann, Katja,Li, Jiyang,Namasivayam, Vigneshwaran,Baltes, Fabian,Bendas, Gerd,Stefan, Sven Marcel,Wiese, Michael
, p. 10412 - 10432 (2020/11/02)
In the search for highly effective modulators addressing ABCG2-mediated MDR, 23 pyrimidines were synthesized and biologically assessed. Seven derivatives with (a) nitrogen- and/or halogen-containing residue(s) had extraordinary potencies against ABCG2 (IC50 150 nM). The compounds competitively inhibited ABCG2-mediated Hoechst 33342 transport but were not substrates of ABCG2. The most potent MDR reverser, compound 19, concentration-dependently increased SN-38-mediated cancer cell death at 11 nM (EC50), time-dependently doubled SN-38 toxicity in a period of 7 days at 10 nM, and half-maximally accelerated cell death combined with SN-38 at 17 nM. No induction of ABCG2 was observed. Furthermore, 11 pyrimidines were revealed as triple ABCB1/ABCC1/ABCG2 inhibitors. Five possessed IC50 values below 10 μM against each transporter, classifying them as some of the 50 most potent multitarget ABC transporter inhibitors. The most promising representative, compound 37, reversed ABCB1-, ABCC1-, and ABCG2-mediated MDR, making it one of the three most potent ABC transporter inhibitors and reversers of ABC transporters-mediated MDR.
NURR1:RXR ACTIVATING COMPOUNDS FOR SIMULTANEOUS TREATMENT OF SYMPTOMS AND PATHOLOGY OF PARKINSON'S DISEASE
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Page/Page column 37; 41, (2017/08/01)
The invention provides a series of substituted aryl pyrimidine compounds and the use of these compounds as therapeutics to treat or prevent neurodegenerative disorders, including Parkinson's disease. Compounds of the invention are also able to treat the s
4-Anilino-2-pyridylquinazolines and -pyrimidines as Highly Potent and Nontoxic Inhibitors of Breast Cancer Resistance Protein (ABCG2)
Krapf, Michael K.,Gallus, Jennifer,Wiese, Michael
, p. 4474 - 4495 (2017/06/05)
Multidrug resistance (MDR) mediated by ATP-binding cassette (ABC) transport proteins remains a major problem in the chemotherapeutic treatment of cancer and might be overcome by inhibition of the transporter. Because of the lack of understanding, the complex mechanisms involved in the transport process, in particular for breast cancer resistance protein (BCRP/ABCG2), there is a persistent need for studies of inhibitors of ABCG2. In this study, we investigated a systematic series of 4-substituted-2-pyridylquinazolines in terms of their inhibitory potency as well as selectivity toward ABCG2. For comparison, the quinazoline scaffold was reduced to the significantly smaller 4-methylpyrimidine basic structure. Furthermore, the cytotoxicity and the ability to reverse MDR was tested with the chemotherapeutic agents SN-38 and mitoxantrone (MX). Interaction of the compounds with ABCG2 was investigated by a colorimetric ATPase assay. Enzyme kinetic studies were carried out with Hoechst 33342 as fluorescent dye and substrate of ABCG2 to elucidate the compounds binding modes.
Pyrimidine derivatives and application thereof
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Paragraph 0091-0093; 0110-0112, (2016/10/20)
The invention discloses compounds of formula (1), and pharmaceutically acceptable salts thereof, and an application of the compounds and the pharmaceutically acceptable salts in prevention and treatment of aches.
Ultrasound-Promoted Synthesis of 4-Pyrimidinols and Their Tosyl Derivatives
Vidal, Matías,García-Arriagada, Macarena,Rezende, Marcos Caroli,Domínguez, Moisés
, p. 4246 - 4252 (2016/11/26)
Ultrasound irradiation promoted the cyclocondensation of β-keto esters and amidines in good to excellent yields to form sixteen highly substituted 4-pyrimidinols. Tosylation of these compounds, in another ultrasound-promoted conversion, formed 4-pyrimidyl tosylates in high yields. The use of the developed protocol as an alternative route to 4-arylpyrimidines was illustrated with three examples of the Suzuki-Miyaura cross-coupling of the prepared tosylates with phenylboronic acid.
Synthesis and biological evaluation of novel sigma-1 receptor antagonists based on pyrimidine scaffold as agents for treating neuropathic pain
Lan, Yu,Chen, Yin,Cao, Xudong,Zhang, Juecheng,Wang, Jie,Xu, Xiangqing,Qiu, Yinli,Zhang, Tan,Liu, Xin,Liu, Bi-Feng,Zhang, Guisen
, p. 10404 - 10423 (2015/02/19)
The discovery and synthesis of a new series of pyrimidines as potent sigma-1 receptor (σ1R) antagonists, associated with pharmacological antineuropathic pain activity, are the focus of this article. The new compounds were evaluated in vitro in σ-1 and σ-2 receptor binding assays. The nature of the pyrimidine scaffold was crucial for activity, and a basic amine was shown to be necessary according to the known pharmacophoric model. The most promising derivative was 5-chloro-2-(4-chlorophenyl)-4-methyl-6-(3-(piperidin-1-yl)propoxy)pyrimidine (137), which exhibited a high binding affinity to σ1R receptor (Ki σ1 = 1.06 nM) and good σ-1/2 selectivity (1344-fold). In in vivo tests, compound 137 exerted dose-dependent antinociceptive effects in mice formalin model and rats CCI models of neuropathic pain. In addition, no motor impairments were found in rotarod tests; acceptable pharmacokinetic properties were also noted. These data suggest compound 137 may constitute a novel class of drugs for the treatment of neuropathic pain.
A convenient synthesis of pyrimidinone and pyrimidine containing bisheteroarenes and analogs
Maurya, Hardesh K.,Gupta, Atul
, p. 22106 - 22114 (2014/06/23)
The synthesis of pyrimidinone containing bisheteroarenes (3) and related analogs (9 and 10) by the reaction of active methylenes or substituted methyl acrylate with nitrogen containing precursors viz. amidines, or thiourea in water as well as other organic solvents was studied. Synthesized compounds have further been explored for the synthesis of diversified pyrimidines 4, 6-8, 11, 12 and 14 through a sequential approach. This journal is the Partner Organisations 2014.
Virtual screening and optimization yield low-nanomolar inhibitors of the tautomerase activity of Plasmodium falciparum macrophage migration inhibitory factor
Dahlgren, Markus K.,Garcia, Alvaro Baeza,Hare, Alissa A.,Tirado-Rives, Julian,Leng, Lin,Bucala, Richard,Jorgensen, William L.
supporting information, p. 10148 - 10159 (2013/01/16)
The Plasmodium falciparum orthologue of the human cytokine, macrophage migratory inhibitory factor (PfMIF), is produced by the parasite during malaria infection and modulates the host's immune response. As for other MIF orthologues, PfMIF has tautomerase activity, whose inhibition may influence the cytokine activity. To identify small-molecule inhibitors of the tautomerase activity of PfMIF, virtual screening has been performed by docking 2.1 million compounds into the enzymatic site. Assaying of 17 compounds identified four as active. Substructure search for the most potent of these compounds, a 4-phenoxypyridine analogue, identified four additional compounds that were purchased and also shown to be active. Thirty-one additional analogues were then designed, synthesized, and assayed. Three were found to be potent PfMIF tautomerase inhibitors with Ki of ～40 nM; they are also highly selective with Ki > 100 μM for human MIF.
Synthesis and structure-activity relationship of 4-amino-2-phenylpyrimidine derivatives as a series of novel GPR119 agonists
Negoro, Kenji,Yonetoku, Yasuhiro,Maruyama, Tatsuya,Yoshida, Shigeru,Takeuchi, Makoto,Ohta, Mitsuaki
experimental part, p. 2369 - 2375 (2012/05/05)
Through preparation and examination of a series of novel 4-amino-2-phenylpyrimidine derivatives as agonists for GPR119, we identified 2-(4-bromophenyl)-6-methyl-N-[2-(1-oxidopyridin-3-yl)ethyl]pyrimidin-4-amine (9t). Compound 9t improved glucose tolerance in mice following oral administration and showed good pharmacokinetic profiles in rats.
Palladium catalyzed ring opening of furans as a route to α,β-unsaturated aldehydes
El Kaim, Laurent,Grimaud, Laurence,Wagschal, Simon
supporting information; experimental part, p. 1887 - 1889 (2011/03/23)
Furans may be ring opened via pallado-catalyzed reactions leading to α,β-unsaturated aldehydes and ketones tethered to indole and isoquinoline moieties. Besides their synthetic interest, these fragmentations bring interesting elements into the discussion
