37660-23-4Relevant academic research and scientific papers
PB-10, a thiazolo[4,5-d] pyrimidine derivative, targets p21-activated kinase 4 in human colorectal cancer cells
Li, Ruijuan,Wang, Hanxun,Wang, Jian,Cheng, Maosheng
, (2019/11/26)
Targeting p21-activated kinase 4 (PAK4) is a potential therapeutic strategy against human colorectal cancer (CRC). In this study, we synthesized a series of novel thiazolo[4,5-d]pyrimidine derivatives (PB-1–12) and identified PB-10 (PAK4 IC50 = 15.12 μM) as a potential and potent PAK4 inhibitor. Our results showed that PB-10 significantly suppressed the proliferation and colony formation of human CRC cells. PB-10 also arrested HCT-116 CRC cells at sub G0/G1 phase while promoting the expression of proapoptotic proteins. In addition, PB-10 inhibited migration, invasion, and adhesion as well as the PAK4 downstream signaling pathway in HCT-116 cells. Molecular docking analysis showed possible binding modes between PB-10 and PAK4. Our study provides a novel compound that may block the PAK4 signaling in CRC cells.
Studies on enantioselectivity of chiral 4-acetylamino-6-alkyloxy-2-alkylthiopyrimidines acting as antagonists of the human A3 adenosine receptor
Cosimelli, Barbara,Greco, Giovanni,Laneri, Sonia,Novellino, Ettore,Sacchi, Antonia,Collina, Simona,Rossi, Daniela,Cosconati, Sandro,Barresi, Elisabetta,Taliani, Sabrina,Trincavelli, Maria Letizia,Martini, Claudia
, p. 81 - 86 (2018/02/07)
Three A3 adenosine receptor (AR) antagonists (1-3) selected from 4-acylamino-6-alkyloxy-2-alkylthiopyrimidines previously investigated by us were modified by inserting a methyl group on their ether or thioether side chains. These compounds gave
Synthesis and preliminary biological evaluation of [11C]methyl (2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-D-leucinate for the fractalkine receptor (CX3CR1)
Gao, Mingzhang,Wang, Min,Meyer, Jill A.,Peters, Jonathan S.,Zarrinmayeh, Hamideh,Territo, Paul R.,Hutchins, Gary D.,Zheng, Qi-Huang
, p. 2727 - 2730 (2017/05/29)
The reference standard methyl (2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-D-leucinate (5) and its precursor 2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-D-leucine (6) were synthesized from 6-amino-2-mercaptopyrimidin-4-ol and BnBr with o
RADIOFLUORINATED 7-AMINO-5-THIO-THIAZOLO[4,5-D]PYRIMIDINES FOR IMAGING FRACTALKINE RECEPTOR (CX3CR1)
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Page/Page column 31, (2016/12/26)
Radiofluorinated 7-Amino-5-thio-thiazolo[4,5-d]pyrimidines targeting Fractalkine Receptor (CX3CR1) are disclosed. Methods of imaging CX3CR1-expressing tumors or cells also are disclosed.
4-amino-6-alkyloxy-2-alkylthiopyrimidine derivatives as novel non-nucleoside agonists for the adenosine A1 receptor
Cosimelli, Barbara,Greco, Giovanni,Laneri, Sonia,Novellino, Ettore,Sacchi, Antonia,Trincavelli, Maria Letizia,Giacomelli, Chiara,Taliani, Sabrina,Da Settimo, Federico,Martini, Claudia
, p. 724 - 729 (2016/10/25)
Three 4-amino-6-alkyloxy-2-alkylthiopyrimidine derivatives (4–6) were investigated as potential non-nucleoside agonists at human adenosine receptors (ARs). When tested in competition binding experiments, these compounds exhibited low micromolar affinity (
Enantiomeric 4-Acylamino-6-alkyloxy-2 Alkylthiopyrimidines As Potential A3Adenosine Receptor Antagonists: HPLC Chiral Resolution and Absolute Configuration Assignment by a Full Set of Chiroptical Spectroscopy
Rossi, Daniela,Nasti, Rita,Marra, Annamaria,Meneghini, Silvia,Mazzeo, Giuseppe,Longhi, Giovanna,Memo, Maurizio,Cosimelli, Barbara,Greco, Giovanni,Novellino, Ettore,Da Settimo, Federico,Martini, Claudia,Taliani, Sabrina,Abbate, Sergio,Collina, Simona
, p. 434 - 440 (2017/02/10)
The chiral separation of enantiomeric couples of three potential A3adenosine receptor antagonists: (R/S)-N-(6-(1-phenylethoxy)-2-(propylthio)pyrimidin-4-yl)acetamide (1), (R/S)-N-(2-(1-phenylethylthio)-6-propoxypyrimidin-4-yl)acetamide (2), and
Discovery and evaluation of a novel monocyclic series of CXCR2 antagonists
Austin, Rupert P.,Bennion, Colin,Bonnert, Roger V.,Cheema, Lal,Cook, Anthony R.,Cox, Rhona J.,Ebden, Mark R.,Gaw, Alasdair,Grime, Ken,Meghani, Premji,Nicholls, David,Phillips, Caroline,Smith, Neal,Steele, John,Stonehouse, Jeffrey P.
, p. 1616 - 1620 (2015/03/30)
Antagonism of the chemokine receptor CXCR2 has been proposed as a strategy for the treatment of inflammatory diseases such as arthritis, chronic obstructive pulmonary disease and asthma. Earlier series of bicyclic CXCR2 antagonists discovered at AstraZene
Synthesis and biological evaluation of imidazo[1,2-a]pyrimidines and imidazo[1,2-a]pyridines as new inhibitors of the Wnt/β-catenin signaling
Cosimelli, Barbara,Laneri, Sonia,Ostacolo, Carmine,Sacchi, Antonia,Severi, Elda,Porcù, Elena,Rampazzo, Elena,Moro, Enrico,Basso, Giuseppe,Viola, Giampietro
, p. 45 - 56 (2014/07/07)
Wnt/β-catenin signaling plays an important role in the regulation of embryonic development and tumorigenesis. Since its deregulation results in severe human diseases, especially cancer, the Wnt signaling pathway constitutes a promising platform for pharmacological targeting of cancer. In this study we synthesized a series of imidazo[1,2-a]pyrimidines and imidazo[1,2-a]pyridines and identified some derivatives that were able to inhibit the Wnt/β-catenin signaling pathway in a luciferase reporter assay and cell proliferation in selected cancer cell lines, endowed with APC or β-catenin gene mutations. The most active compounds significantly downregulate the expression of Wnt target genes such as c-myc and cyclin D1. Further studies indicated that these compounds function independently of GSK-3β activity. More importantly, in vivo experiments, carried out on a Wnt-reporter zebrafish model indicate, in particular for compounds 4c and 4i as the most active compounds, an activity comparable to that of the reference compound IWR1, suggesting their potential use not only as small molecule inhibitors of the Wnt/β-catenin signal in Wnt driven cancers, but also in other Wnt-related diseases.
Substituted 7-amino-5-thio-thiazolo[4,5- d ]pyrimidines as potent and selective antagonists of the fractalkine receptor (CX3CR1)
Karlstr?m, Sofia,Nordvall, Gunnar,Sohn, Daniel,Hettman, Andreas,Turek, Dominika,?hlin, Kristofer,Kers, Annika,Claesson, Martina,Slivo, Can,Lo-Alfredsson, Yvonne,Petersson, Carl,Bessidskaia, Galina,Svensson, Per H.,Rein, Tobias,Jerning, Eva,Malmberg, ?sa,Ahlgen, Charlotte,Ray, Colin,Vares, Lauri,Ivanov, Vladimir,Johansson, Rolf
, p. 3177 - 3190 (2013/06/05)
We have developed two parallel series, A and B, of CX3CR1 antagonists for the treatment of multiple sclerosis. By modifying the substituents on the 7-amino-5-thio-thiazolo[4,5-d]pyrimidine core structure, we were able to achieve compounds with high selectivity for CX3CR1 over the closely related CXCR2 receptor. The structure-activity relationships showed that a leucinol moiety attached to the core-structure in the 7-position together with α-methyl branched benzyl derivatives in the 5-position displayed promising affinity, and selectivity as well as physicochemical properties, as exemplified by compounds 18a and 24h. We show the preparation of the first potent and selective orally available CX3CR1 antagonists.
Discovery and optimization of aminopyrimidinones as potent and state-dependent Nav1.7 antagonists
Nguyen, Hanh Nho,Bregman, Howie,Buchanan, John L.,Du, Bingfan,Feric, Elma,Huang, Liyue,Li, Xingwen,Ligutti, Joseph,Liu, Dong,Malmberg, Annika B.,Matson, David J.,McDermott, Jeff S.,Patel, Vinod F.,Wilenkin, Ben,Zou, Anruo,McDonough, Stefan I.,Dimauro, Erin F.
supporting information; experimental part, p. 1055 - 1060 (2012/03/26)
Clinical genetic data have shown that the product of the SCN9A gene, voltage-gated sodium ion channel Nav1.7, is a key control point for pain perception and a possible target for a next generation of analgesics. Sodium channels, however, historically have been difficult drug targets, and many of the existing structure-activity relationships (SAR) have been defined on pharmacologically modified channels with indirect reporter assays. Herein we describe the discovery, optimization, and SAR of potent aminopyrimidinone Nav1.7 antagonists using electrophysiology-based assays that measure the ligand-receptor interaction directly. Within this series, rapid functionalization at the polysubstituted aminopyrimidinone head group enabled exploration of SAR and of pharmacokinetic properties. Lead optimized N-Me-aminopyrimidinone 9 exhibited improved Nav1.7 potency, minimal off-target hERG liability, and improved rat PK properties.
