66129-60-0Relevant articles and documents
Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds
Pallesen, Jakob S.,Narayanan, Dilip,Tran, Kim T.,Solbak, Sara M. ?.,Marseglia, Giuseppe,S?rensen, Louis M. E.,H?j, Lars J.,Munafò, Federico,Carmona, Rosa M. C.,Garcia, Anthony D.,Desu, Haritha L.,Brambilla, Roberta,Johansen, Tommy N.,Popowicz, Grzegorz M.,Sattler, Michael,Gajhede, Michael,Bach, Anders
supporting information, p. 4623 - 4661 (2021/05/07)
Targeting the protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-molecule Keap1-Nrf2 PPI inhibitors were dissected into 77 fragments in a fragment-based deconstruction reconstruction (FBDR) study and tested in four orthogonal assays. This gave 17 fragment hits of which six were shown by X-ray crystallography to bind in the Keap1 Kelch binding pocket. Two hits were merged into compound 8 with a 220-380-fold stronger affinity (Ki = 16 μM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with Ki values of 0.04-0.5 μM, binding modes determined by X-ray crystallography, and enhanced microsomal stability. This demonstrates how FBDR can be used to find new fragment hits, elucidate important ligand-protein interactions, and identify new potent inhibitors of the Keap1-Nrf2 PPI.
Discovery and Optimization of 2 H-1λ2-Pyridin-2-one Inhibitors of Mutant Isocitrate Dehydrogenase 1 for the Treatment of Cancer
Rohde, Jason M.,Karavadhi, Surendra,Pragani, Rajan,Liu, Li,Fang, Yuhong,Zhang, Weihe,McIver, Andrew,Zheng, Hongchao,Liu, Qingyang,Davis, Mindy I.,Urban, Daniel J.,Lee, Tobie D.,Cheff, Dorian M.,Hollingshead, Melinda,Henderson, Mark J.,Martinez, Natalia J.,Brimacombe, Kyle R.,Yasgar, Adam,Zhao, Wei,Klumpp-Thomas, Carleen,Michael, Sam,Covey, Joseph,Moore, William J.,Stott, Gordon M.,Li, Zhuyin,Simeonov, Anton,Jadhav, Ajit,Frye, Stephen,Hall, Matthew D.,Shen, Min,Wang, Xiaodong,Patnaik, Samarjit,Boxer, Matthew B.
, p. 4913 - 4946 (2021/05/07)
Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are oncogenic for a number of malignancies, primarily low-grade gliomas and acute myeloid leukemia. We report a medicinal chemistry campaign around a 7,7-dimethyl-7,8-dihydro-2H-1λ2-quinoline-2,5(6H)-dione screening hit against the R132H and R132C mutant forms of isocitrate dehydrogenase (IDH1). Systematic SAR efforts produced a series of potent pyrid-2-one mIDH1 inhibitors, including the atropisomer (+)-119 (NCATS-SM5637, NSC 791985). In an engineered mIDH1-U87-xenograft mouse model, after a single oral dose of 30 mg/kg, 16 h post dose, between 16 and 48 h, (+)-119 showed higher tumoral concentrations that corresponded to lower 2-HG concentrations, when compared with the approved drug AG-120 (ivosidenib).
PYRAZOLOPYRIMIDINE COMPOUND AS PI3K INHIBITOR AND USE THEREOF
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Paragraph 0072-0073, (2019/08/30)
The present application relates to a pyrazolopyrimidine compound of Formula (I) and a pharmaceutically acceptable salt thereof. Such compounds can be used to inhibit the activity of a lipid kinase PI3K, and can also be used to treat diseases mediated by P
Ultrasound assisted synthesis of 2-alkynyl pyrazolo[1,5-a]pyrimidines as potential anti-cancer agents
Bharath, Yarlagadda,Rao, Mandava V. Basaveswara,Pal, Manojit
, p. 1206 - 1214 (2017/11/14)
Background: The 2-alkynyl pyrazolo[1,5-a]pyrimidine derivatives have been explored as new and potential anti-proliferative agents. Methods: Ultrasound assisted synthesis of these compounds was carried out by using a multi-step method involving the H3PO3 mediated construction of pyrazolo[1,5-a]pyrimidine ring possessing a bromo group at C-2 position followed by Pd/C-Cu catalyzed alkynylation methodology as the key steps. Results and Conclusion: All these compounds showed selective growth inhibition of cancer cell lines when tested against MDA-MB 231 and K562 cell lines along with non-cancerous HEK293 cells.
Design, synthesis and RON receptor tyrosine kinase inhibitory activity of new head groups analogs of LCRF-0004
Raeppel, Franck,Raeppel, Stéphane L.,Therrien, Eric
, p. 3810 - 3815 (2015/08/24)
New heteroarylcarboxamide head groups substituted with two aromatic rings analogs of thieno[3,2-b]pyridine-based kinase inhibitor LCRF-0004 were designed and synthesized. Potent inhibitors of RON tyrosine kinase with various level of selectivity for c-Met RTK were obtained.
Isatin-pyrazole benzenesulfonamide hybrids potently inhibit tumor-associated carbonic anhydrase isoforms IX and XII
Ibrahim, Hany S.,Abou-Seri, Sahar M.,Tanc, Muhammet,Elaasser, Mahmoud M.,Abdel-Aziz, Hatem A.,Supuran, Claudiu T.
, p. 583 - 593 (2015/10/19)
New series of benzenesulfonamide derivatives incorporating pyrazole and isatin moieties were prepared using celecoxib as lead molecule. Biological evaluation of the target compounds was performed against the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and more precisely against the human isoforms hCA I, II (cytosolic), IX and XII (transmembrane, tumor-associated enzymes). Most of the tested compounds efficiently inhibited hCA I, II and IX, with KIs of 2.5-102 nM, being more effective than the reference drug acetazolamide. Compounds 11e, 11f, 16e and 16f were found to inhibit hCA XII with Ki of 3.7, 6.5, 5.4 and 7.2 nM, respectively. Compounds 11e and 16e, with 5-NO2substitution on the isatin ring, were found to be selective inhibitors of hCA IX and hCA XII. Docking studies revealed that the NO2group of both compounds participate in interactions with Asp132 within the hCA IX active site, and with residues Lys67 and Asp130 in hCA XII, respectively.
New selective carbonic anhydrase IX inhibitors: Synthesis and pharmacological evaluation of diarylpyrazole-benzenesulfonamides
Rogez-Florent, Tiphaine,Meignan, Samuel,Foulon, Catherine,Six, Perrine,Gros, Abigaelle,Bal-Mahieu, Christine,Supuran, Claudiu T.,Scozzafava, Andrea,Frederick, Raphael,Masereel, Bernard,Depreux, Patrick,Lansiaux, Amelie,Goossens, Jean-Francois,Gluszok, Sebastien,Goossens, Laurence
, p. 1451 - 1464 (2013/04/10)
Carbonic anhydrase (CA) IX expression is increased upon hypoxia and has been proposed as a therapeutic target since it has been associated with poor prognosis, tumor progression and pH regulation. We report the synthesis and the pharmacological evaluation
Synthesis, characterization and antimicrobial activity of novel ethyl 1-(N-substituted)-5-phenyl-1H-pyrazole-4-carboxylate derivatives
Chandrakantha,Isloor, Arun M.,Shetty, Prakash,Isloor, Shrikrishna,Malladi, Shridhar,Fun, Hoong Kun
, p. 2702 - 2708 (2012/10/30)
In the present study, a novel series of Pyrazole derivatives (3a-m) were synthesized by condensing ethyl-3-(dimethylamino)-2-(phenylcarbonyl)prop-2- enoate with different aromatic and aliphatic hydrazines. These newly synthesized compounds were characteri
Optimisation of pharmacokinetic properties in a neutral series of 11β-HSD1 inhibitors
Scott, James S.,Gill, Adrian L.,Godfrey, Linda,Groombridge, Sam D.,Rees, Amanda,Revill, John,Schofield, Paul,S?rme, Pernilla,Stocker, Andrew,Swales, John G.,Whittamore, Paul R.O.
, p. 6756 - 6761 (2013/01/14)
11β-HSD1 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. In this program of work we describe how a series of neutral 2-thioalkyl-pyridine 11β-HSD1 inhibitors were optimized in terms of their pharmacokinetic properties to give compounds with excellent bioavailability in both rat and dog through a core change to pyrimidine. A potential reactive metabolite issue with 4-thioalkyl-pyrimidines was circumvented by a switch from sulfur to carbon substitution.
(Pd/C-mediated)coupling-iodocyclization-coupling strategy in discovery of novel PDE4 inhibitors: A new synthesis of pyrazolopyrimidines
Kumar, P. Mahesh,Kumar, K. Siva,Meda, Chandana L.T.,Reddy, G. Rajeshwar,Mohakhud, Pradeep K.,Mukkanti,Krishna, G. Rama,Reddy, C. Malla,Rambabu,Kumar, K. Shiva,Priya, K. Krishna,Chennubhotla, Keerthana Sarma,Banote, Rakesh Kumar,Kulkarni, Pushkar,Parsa, Kishore V.L.,Pal, Manojit
supporting information, p. 667 - 672 (2013/11/06)
Pyranones fused with a pyrazolopyrimidine moiety were prepared via regioselective construction of pyranone ring using (Pd/C-mediated)coupling- iodocyclization followed by Sonogashira/Heck/Suzuki reactions. The pyrazolopyrimidine based reactant required was obtained via a new H 3PO3 mediated condensation reaction. This strategy has led to the discovery of a novel and potentially safe PDE4 inhibitor.
