- WEE1 KINASE INHIBITORS AND METHODS OF TREATING CANCER USING THE SAME
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A compound, or a pharmaceutically acceptable salts or prodrugs thereof, having the chemical structure (I) and methods of using these compounds to inhibit WEE1 kinase and treat cancer in a subject.
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Page/Page column 48-49
(2019/09/18)
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- Development of Potent Pyrazolopyrimidinone-Based WEE1 Inhibitors with Limited Single-Agent Cytotoxicity for Cancer Therapy
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WEE1 kinase regulates the G2/M cell-cycle checkpoint, a critical mechanism for DNA repair in cancer cells that can confer resistance to DNA-damaging agents. We previously reported a series of pyrazolopyrimidinones based on AZD1775, a known WEE1 inhibitor, as an initial investigation into the structural requirements for WEE1 inhibition. Our lead inhibitor demonstrated WEE1 inhibition in the same nanomolar range as AZD1775, and potentiated the effects of cisplatin in medulloblastoma cells, but had reduced single-agent cytotoxicity. These results prompted the development of a more comprehensive series of WEE1 inhibitors. Herein we report a series of pyrazolopyrimidinones and identify a more potent WEE1 inhibitor than AZD1775 and additional compounds that demonstrate that WEE1 inhibition can be achieved with reduced single-agent cytotoxicity. These studies support that WEE1 inhibition can be uncoupled from the potent cytotoxic effects observed with AZD1775, and this may have important ramifications in the clinical setting where WEE1 inhibitors are used as chemosensitizers for DNA-targeted chemotherapy.
- Matheson, Christopher J.,Casalvieri, Kimberly A.,Backos, Donald S.,Reigan, Philip
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supporting information
p. 1681 - 1694
(2018/08/01)
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- Thieno[3,2-b]pyrrole-5-carboxamides as New Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 1: High-Throughput Screening and Preliminary Exploration
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Lysine specific demethylase 1 KDM1A (LSD1) regulates histone methylation and it is increasingly recognized as a potential therapeutic target in oncology. We report on a high-throughput screening campaign performed on KDM1A/CoREST, using a time-resolved fluorescence resonance energy transfer (TR-FRET) technology, to identify reversible inhibitors. The screening led to 115 hits for which we determined biochemical IC50, thus identifying four chemical series. After data analysis, we have prioritized the chemical series of N-phenyl-4H-thieno[3, 2-b]pyrrole-5-carboxamide for which we obtained X-ray structures of the most potent hit (compound 19, IC50 = 2.9 μM) in complex with the enzyme. Initial expansion of this chemical class, both modifying core structure and decorating benzamide moiety, was directed toward the definition of the moieties responsible for the interaction with the enzyme. Preliminary optimization led to compound 90, which inhibited the enzyme with a submicromolar IC50 (0.162 μM), capable of inhibiting the target in cells.
- Sartori, Luca,Mercurio, Ciro,Amigoni, Federica,Cappa, Anna,Fagá, Giovanni,Fattori, Raimondo,Legnaghi, Elena,Ciossani, Giuseppe,Mattevi, Andrea,Meroni, Giuseppe,Moretti, Loris,Cecatiello, Valentina,Pasqualato, Sebastiano,Romussi, Alessia,Thaler, Florian,Trifiró, Paolo,Villa, Manuela,Vultaggio, Stefania,Botrugno, Oronza A.,Dessanti, Paola,Minucci, Saverio,Zagarrí, Elisa,Carettoni, Daniele,Iuzzolino, Lucia,Varasi, Mario,Vianello, Paola
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supporting information
p. 1673 - 1692
(2017/03/17)
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- Discovery of Potent, Selective Stem Cell Factor Receptor/Platelet Derived Growth Factor Receptor Alpha (c-KIT/PDGFRα) Dual Inhibitor for the Treatment of Imatinib-Resistant Gastrointestinal Stromal Tumors (GISTs)
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Stem cell factor receptor (c-KIT) and platelet derived growth factor receptor alpha (PDGFRα) kinases play an important role in gastrointestinal stromal tumors (GISTs). Here, we have discovered an c-KIT/PDGFRα dual inhibitor, compound 31, with single-digit nanomolar potency against c-KIT and PDGFRα. Compared to Imatinib (1), 31 showed better antiproliferative efficacy against various TEL-c-KIT/PDGFRα-BaF3 isogenic cells, including three 1-resistant BaF3 cell lines, as well as against GIST-T1 and GIST-882 cell lines. Furthermore, compound 31 showed a good KinomeScan selectivity (468 kinases) (S score (1) = 0.01 at 1 μM concentration), good metabolic stability in liver microsomes, and no hERG inhibitory activity. It was worth noting that 31 inhibited GIST-T1 tumor growth (TGI = 81.5%) and even the BaF3-TEL-cKIT-T670I tumor progression (TGI = 41.9%, 1-resistant GISTs) at a dosage of 100 mg/kg/day without exhibiting apparent toxicity.
- Lu, Yanli,Mao, Fei,Li, Xiaokang,Zheng, Xinyu,Wang, Manjiong,Xu, Qing,Zhu, Jin,Li, Jian
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supporting information
p. 5099 - 5119
(2017/06/28)
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- Hydrogenation of (N,N-disubstituted aminomethyl)nitrobenzenes to (N,N-disubstituted aminomethyl)anilines catalyzed by palladium-nickel bimetallic nanoparticles
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Since palladium-catalysts have strong abilities for both hydrogenation of nitro-group and hydrogenolysis of benzylamine, they have a much lower chemoselectivity for the hydrogenation of (N,N-disubstituted aminomethyl)nitrobenzenes. In this article, component stable Pd-Ni bimetallic nanoparticles were prepared by simply heating RANEY-Ni and Na2PdCl4 together in water. They demonstrated novel synergistic effects when they were used as a bimetallic catalyst, by which a highly efficient and chemoselective hydrogenation of (N,N-disubstituted aminomethyl)nitrobenzenes to (N,N-disubstituted aminomethyl)anilines was achieved.
- Bao, Hailin,Wang, Dingsheng,Wang, Xinyan,Cheng, Chuanjie,Li, Yadong,Hu, Yuefei
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p. 47125 - 47130
(2015/06/16)
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- Phenyl ether- and aniline-containing 2-aminoquinolines as potent and selective inhibitors of neuronal nitric oxide synthase
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Excess nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) is implicated in neurodegenerative disorders. As a result, inhibition of nNOS and reduction of NO levels is desirable therapeutically, but many nNOS inhibitors are poorly bioavailable. Promising members of our previously reported 2-aminoquinoline class of nNOS inhibitors, although orally bioavailable and brain-penetrant, suffer from unfavorable off-target binding to other CNS receptors, and they resemble known promiscuous binders. Rearranged phenyl ether- and aniline-linked 2-aminoquinoline derivatives were therefore designed to (a) disrupt the promiscuous binding pharmacophore and diminish off-target interactions and (b) preserve potency, isoform selectivity, and cell permeability. A series of these compounds was synthesized and tested against purified nNOS, endothelial NOS (eNOS), and inducible NOS (iNOS) enzymes. One compound, 20, displayed high potency, selectivity, and good human nNOS inhibition, and retained some permeability in a Caco-2 assay. Most promisingly, CNS receptor counterscreening revealed that this rearranged scaffold significantly reduces off-target binding.
- Cinelli, Maris A.,Li, Huiying,Pensa, Anthony V.,Kang, Soosung,Roman, Linda J.,Martásek, Pavel,Poulos, Thomas L.,Silverman, Richard B.
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supporting information
p. 8694 - 8712
(2015/11/25)
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- IMIDAZOPYRIDINES AS A NOVEL SCAFFOLD FOR MULTI-TARGETED KINASE INHIBITION
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Compounds that inhibit protein kinases, compositions containing the compounds and methods of treating diseases using the compounds are disclosed. Formula (I).
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Page/Page column 163
(2011/05/11)
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- QUINOLINE DERIVATIVES
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The invention concerns quinoline derivatives of Formula (I): or a pharmaceutically-acceptable salt thereof, wherein each of X1, p, R1, q, R2, R3, R4, R5, Ring A, r and R6 has any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use in the treatment of cell proliferative disorders.
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Page/Page column 141-142
(2008/06/13)
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- QUINAZOLINE DERIVATIVES
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The invention concerns quinazoline derivatives of Formula (I) or a pharmaceutically-acceptable salt, solvate or pro-drug thereof, wherein each of X1, p, R1, q, R2, R3, R4, R5, Ring A, r and R6 has any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use in the treatment of cell proliferative disorders or in the treatment of disease states associated with angiogenesis and/or vascular permeability.
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Page/Page column 92
(2008/06/13)
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- QUINOLINE DERIVATIVES
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The invention concerns quinoline derivatives of Formula (I) or a pharmaceutically-acceptable salt, solvate or pro-drug thereof, wherein each of p, R1, q, R2, R3, R4, R5, Ring A, r and R6 has any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use in the treatment of cell proliferative disorders or in the treatment of disease states associated with angiogenesis and/or vascular permeability.
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Page/Page column 85
(2008/06/13)
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- QUINAZOLINE DERIVATIVES FOR USE AGAINST CANCER
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The invention concerns quinazoline derivatives of Formula (I) or a pharmaceutically-acceptable salt, solvate or pro-drug thereof, wherein each of p, R1, q, R2, R3, R4, R5, Ring A, X1, R6, r and R7 has any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use in the treatment of cell proliferative disorders or in the treatment of disease states associated with angiogenesis and/or vascular permeability.
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Page/Page column 91
(2008/06/13)
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- Pyridine, pyrimidine, quinoline, quinazoline, and naphthalene urotensin-II receptor antagonists
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The present invention relates to urotensin II receptor antagonists, pharmaceutical compositions containing them and their use.
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- Substituted indolines which inhibit receptor tyrosine kinases
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Indolinones of the formula having an inhibitory effect on receptor tyrosine kinases and cyclin/CDK complexes, as well as on the proliferation of endothelial cells and various tumor cells. Exemplary are: (a) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone, (b) 3-Z-[(1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone, and (c) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-metboxycarbonyl-2-indolinone.
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Page column 47
(2008/06/13)
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- Aniline derivatives possessing an inhibitory effect of nitric oxide synthase
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Compounds represented by the general formula (1): ? (where R1is SR6or NR7R8, where R6is typically an alkyl group having 1-6 carbon atoms, R7is a hydrogen atom, an alkyl group having 1-6 carbon atoms or a nitro group, and R8is a hydrogen atom or an alkyl group having 1-6 carbon atoms; R2and R3are each typically a hydrogen atom or an alkyl group having 1-6 carbon atoms; R4is a hydrogen atom, an alkyl group having 1-6 carbon atoms or an amidino group of which the amine portion may be substituted by an alkyl or nitro group; R5is a hydrogen atom or an alkyl group having 1-6 carbon atoms; Y1, Y2, Y3and Y4which may be the same or different are each typically a hydrogen atom, a halogen atom or an alkoxy group having 1-6 carbon atoms; n and m are each an integer of 0 or 1), or possible stereoisomers or optically active forms of the compounds or pharmaceutically acceptable salts thereof. The compounds possess a potent nitric oxide synthase inhibiting activity and are useful as therapeutics of cerebrovascular diseases.
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- N-phenylamidines as selective inhibitors of human neuronal nitric oxide synthase: Structure-activity studies and demonstration of in vivo activity
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Selective inhibition of the neuronal isoform of nitric oxide synthase (NOS) compared to the endothelial and inducible isoforms may be required for treatment of neurological disorders caused by excessive production of nitric oxide. Recently, we described N-(3-(aminomethyl)benzyl)acetamidine (13) as a slow, tight-binding inhibitor, highly selective for human inducible nitric oxide synthase (iNOS). Removal of a single methylene bridge between the amidine nitrogen and phenyl ring to give N-(3- (aminomethyl)phenyl)acetamidine (14) dramatically altered the selectivity to give a neuronal selective nitric oxide synthase (nNOS) inhibitor. Part of this large shift in selectivity was due to 14 being a rapidly reversible inhibitor of iNOS in contrast to the essentially irreversible inhibition of iNOS observed with 13. Structure-activity studies revealed that a basic amine functionality tethered to an aromatic ring and a sterically compact amidine are key pharmacophores for this class of NOS inhibitors. Maximal nNOS inhibition potency was achieved with N-(3-(aminomethyl)phenyl)-2- furanylamidine (77) (K(i-nNOS) = 0.006 μM; K(i-eNOS) = 0.35 μM; K(i-iNOS) = 0.16 μM). Finally, α-fluoro-N-(3-(aminomethyl)phenyl)acetamidine (74) (K(i- nNOS) = 0.011 μM; K(i-eNOS) = 1.1 μM; K(i-iNOS) = 0.48 μM) had excellent brain penetration and inhibited nNOS in a rat brain slice assay as well as in the rat brain (cerebellum) in vivo. Thus, N-phenylamidines should be useful in validating the role of nNOS in neurological disorders.
- Collins, Jon L.,Shearer, Barry G.,Oplinger, Jeffrey A.,Lee, Shuliang,Garvey, Edward P.,Salter, Mark,Duffy, Claire,Burnette, Thimysta C.,Furfine, Eric S.
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p. 2858 - 2871
(2007/10/03)
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- CATECHOLAMINE SURROGATES USEFUL AS BETA 3 AGONISTS
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Compounds of the formula STR1 and pharmaceutically acceptable salts thereof. These compounds are beta three adrenergic receptor agonists and are useful, therefore for example, in the treatment of diabetes, obesity and gastrointestinal diseases.
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- POTENTIAL ANTIDEPRESSANTS. SYNTHESIS OF 6,11-DIHYDRODIBENZOTHIEPIN-11-YL (DIMETHYLAMINOMETHYL)PHENYL ETHERS, SULFIDES, AMINES AND SOME RELATED COMPOUNDS
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Reactions of 11-chloro-6,11-dihydrodibenzothiepin and its 2-bromo derivative with the isomeric (dimethylaminomethyl)phenols, (dimethylaminomethyl)thiophenols, and (dimethylaminomethyl)anilines in toluene afforded the title compounds IIIb,c, Va, VIIIa,b,c, and Xa,b,c.Reactions of 11-chloro-6,11-dihydrodibenzothiepin and its 2-chloro and 2-methyl derivatives with N,N-dimethyl-2-(4-aminophenoxy)ethylamine and N,N-dimethyl-3-(4-aminophenoxy)propylamine by heating in dimethylformamide in the presence of sodium carbonate gave the diamino ethers XI-XIV.Thecompounds showed only indications of the antidepressant agents profile and some antimicrobial effects in vitro.
- Sindelar, Karel,Valenta, Vladimir,Holubek, Jiri,Matousova, Oluse,Protiva, Miroslav
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p. 282 - 295
(2007/10/02)
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