- Phenanthridin-6-one derivatives as the first class of non-steroidal pharmacological chaperones for Niemann-Pick disease type C1 protein
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Niemann-Pick disease type C is a fatal, progressive neurodegenerative disease mostly caused by mutations in Nieamnn-Pick type C1 (NPC1), a late endosomal membrane protein that is essential for intracellular cholesterol transport. The most prevalent mutation, I1061T (Ile to Thr), interferes with the protein folding process. Consequently, mutated but intrinsically functional NPC1 proteins are prematurely degraded via proteasome, leading to loss of NPC1 function. Previously, we reported sterol derivatives as pharmacological chaperones for NPC1, and showed that these derivatives can normalize folding-defective phenotypes of I1061T NPC1 mutant by directly binding to, and stabilizing, the protein. Here, we report a series of compounds containing a phenanthridin-6-one scaffold as the first class of non-steroidal pharmacological chaperones for NPC1. We also examined their structure-activity relationships.
- Fukuda, Hiromitsu,Karaki, Fumika,Dodo, Kosuke,Noguchi-Yachide, Tomomi,Ishikawa, Minoru,Hashimoto, Yuichi,Ohgane, Kenji
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Read Online
- QUINOXALINE DERIVATIVES
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The present invention relates to compounds according to general formula (I), which act as modulators of the glucocorticoid receptor and can be used in the treatment and/or prophylaxis of disorders which are at least partially mediated by the glucocorticoid receptor.
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Page/Page column 65
(2021/07/24)
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- Biphenyl compound as well as preparation method and medical application thereof
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The invention discloses a biphenyl compound as well as a preparation method and medical application thereof, the structure of the biphenyl compound is shown as a formula (I) or a formula (II), and thebiphenyl compound or pharmaceutically acceptable salt, tautomer, meso-isomer, raceme, stereoisomer, metabolite, metabolite precursor, prodrug or solvate thereof is a PD-L1 inhibitor. The compound hasa remarkable inhibiting effect on the interaction of PD-1 and PD-L1 protein, so that the compound can be applied to the preparation of PD-L1 inhibitors and immunomodulator drugs for preventing or treating tumors, autoimmune diseases, organ transplant rejection, infectious diseases and inflammatory diseases.
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Paragraph 0297-0303; 0579-0585
(2020/11/22)
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- SUBSTITUTED TRIAZOLO QUINOXALINE DERIVATIVES
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The present invention relates to compounds according to general formula (I) which act as modulators of the glucocorticoid receptor and can be used in the treatment and/or prophylaxis of disorders which are at least partially mediated by the glucocorticoid receptor.
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Page/Page column 85
(2020/02/14)
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- HERBICIDAL CINNOLINIUM COMPOUNDS
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Compounds of the formula (I) wherein the substituents are as defined in claim 1, useful as a pesticides, especially as herbicides.
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Page/Page column 69
(2020/07/14)
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- Discovery of VU6027459: A First-in-Class Selective and CNS Penetrant mGlu7Positive Allosteric Modulator Tool Compound
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Herein, we report the discovery of the first selective and CNS penetrant mGlu7 PAM (VU6027459) derived from a "molecular switch"within a selective mGlu7 NAM chemotype. VU6027459 displayed CNS penetration in both mice (Kp = 2.74) and rats (Kp= 4.78), it was orally bioavailable in rats (%F = 69.5), and undesired activity at DAT was ablated.
- Reed, Carson W.,Kalbfleisch, Jacob J.,Wong, Madison J.,Washecheck, Jordan P.,Hunter, Ashton,Rodriguez, Alice L.,Blobaum, Anna L.,Conn, P. Jeffrey,Niswender, Colleen M.,Lindsley, Craig W.
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supporting information
p. 1773 - 1779
(2020/10/19)
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- Benzoxadiazole compound and preparation method and medical use thereof
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The invention discloses a benzoxadiazole compound and a preparation method and medical use thereof. The benzoxadiazole compound has the general structure shown in formula (I). The compound or pharmaceutically acceptable salts, tautomers, mesomers, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates of the benzoxadiazole compound have an obvious inhibiting effect on PD-1/PD-L1 protein-protein interaction, so that the benzoxadiazole compound shown in the description can be applied to the preparation of an inhibitor with a PD-1/ PD-L1 inhibitory activity and the immunotherapy of tumors as an immunocheckpoint inhibitor.
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Paragraph 0216-0222
(2019/06/07)
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- EBNA1 INHIBITORS AND THEIR METHOD OF USE
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Pharmaceutical compositions of the invention comprise EBNA1 inhibitors useful for the treatment of diseases caused by EBNA1 activity such as cancer, infectious mononucleosis, chronic fatigue syndrome, multiple sclerosis, systemic lupus erythematosus and rheumatoid arthritis. Pharmaceutical compositions of the invention also comprise EBNA1 inhibitors useful for the treatment of diseases caused by latent Epstein-Barr Virus (EBV) infection. Pharmaceutical compositions of the invention also comprise EBNA1 inhibitors useful for the treatment of diseases caused by lytic Epstein-Barr Virus (EBV) infection.
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Paragraph 0253-0254; 0413
(2015/06/03)
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- Ammonium chloride-catalyzed one-pot synthesis of 4(3H)-quinazolinones under solvent-free conditions
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Ammonium chloride, which is a very inexpensive and readily available reagent, can efficiently catalyze three-component, one-pot condensation reactions of 2-amino-benzoic acid esters, ortho esters, and aromatic amines to afford the corresponding 4(3H)-quinazolinones in good to excellent yields under solvent-free conditions.
- Huang, Guoli,Liu, Bo,Teng, Mingyu,Chen, Yegao
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supporting information
p. 1786 - 1794
(2014/06/09)
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- Synthesis and biological evaluation of thieno[3,2-d]- pyrimidinones, thieno[3,2-d]pyrimidines and quinazolinones: Conformationally restricted 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) inhibitors
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In this study, a series of conformationally restricted thieno[3,2-d] pyrimidinones, thieno[3,2-d]pyrimidines and quinazolinones was designed and synthesized with the goal of improving the biological activity as 17β-hydroxysteroid dehydrogenase type 2 inhi
- Perspicace, Enrico,Marchais-Oberwinkler, Sandrine,Hartmann, Rolf W.
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p. 4487 - 4509
(2013/06/05)
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- Quinazolines with intra-molecular hydrogen bonding scaffold (iMHBS) as PI3K/mTOR dual inhibitors
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Intra-molecular hydrogen bonding was introduced to the quinazoline motif to form a pseudo ring (intra-molecular H-bond scaffold, iMHBS) to mimic our previous published core structures, pyrido[2.3-D]pyrimidin-7-one and pteridinone, as PI3K/mTOR dual inhibitors. This design results in potent PI3K/mTOR dual inhibitors and the purposed intra-molecular hydrogen bonding structure is well supported by co-crystal structure in PI3Kγ enzyme. In addition, a novel synthetic route was developed for these analogs.
- Liu, Kevin K.C.,Huang, Xiaojun,Bagrodia, Shubha,Chen, Jeffrey H.,Greasley, Samantha,Cheng, Hengmiao,Sun, Shaoxian,Knighton, Dan,Rodgers, Caroline,Rafidi, Kristina,Zou, Aihua,Xiao, Jiezhan,Yan, Shengyong
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scheme or table
p. 1270 - 1274
(2011/04/16)
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- CONDENSED QUINOLINES AS PROTEIN KINASE MODULATORS
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The invention relates in part to molecules of formula (I) having certain biological activities that include, but are not limited to, inhibiting cell proliferation, modulating protein kinase activity and modulating polymerase activity. Molecules of the inv
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Page/Page column 59
(2011/04/14)
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- NOVEL TRICYCLIC PROTEIN KINASE MODULATORS
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The invention provides compounds that inhibit CK2 and/or Pim kinases and compositions containing such compounds. These tricyclic compounds and compositions containing them are useful for treating proliferative disorders such as cancer, as well as other ki
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Page/Page column 31
(2011/04/18)
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- Discovery and SAR of 5-(3-Chlorophenylamino)benzo[ c ][2,6]naphthyridine-8- carboxylic Acid (CX-4945), the first clinical stage inhibitor of protein kinase CK2 for the Treatment of Cancer
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Herein we chronicle the discovery of CX-4945 (25n), a first-in-class, orally bioavailable ATP-competitive inhibitor of protein kinase CK2 in clinical trials for cancer. CK2 has long been considered a prime cancer drug target because of the roles of deregulated and overexpressed CK2 in cancer-promoting prosurvival and antiapoptotic pathways. These biological properties as well as the suitability of CK2s small ATP binding site for the design of selective inhibitors, led us to fashion novel therapeutic agents for cancer. The optimization leading to 25n (Ki = 0.38 nM) was guided by molecular modeling, suggesting a strong binding of 25n resulting from a combination of hydrophobic interactions, an ionic bridge with Lys68, and hydrogen bonding with the hinge region. 25n was found to be highly selective, orally bioavailable across species (20-51%) and efficacious in xenograft models. The discovery of 25n will allow the therapeutic targeting of CK2 in humans for the first time.
- Pierre, Fabrice,Chua, Peter C.,Obrien, Sean E.,Siddiqui-Jain, Adam,Bourbon, Pauline,Haddach, Mustapha,Michaux, Jerome,Nagasawa, Johnny,Schwaebe, Michael K.,Stefan, Eric,Vialettes, Anne,Whitten, Jeffrey P.,Chen, Ta Kung,Darjania, Levan,Stansfield, Ryan,Anderes, Kenna,Bliesath, Josh,Drygin, Denis,Ho, Caroline,Omori, May,Proffitt, Chris,Streiner, Nicole,Trent, Katy,Rice, William G.,Ryckman, David M.
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experimental part
p. 635 - 654
(2011/03/21)
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- PROTEIN KINASE MODULATORS
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The invention relates in part to molecules having certain biological activities that include, but are not limited to, inhibiting cell proliferation, modulating protein kinase activity and modulating polymerase activity. Molecules of the invention can modulate Pim kinase activity and/or FMS-like tyrosine kinase (Flt) activity. The invention also relates in part to methods for using such molecules.
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Page/Page column 298
(2009/10/01)
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- Alpha-helical mimetics
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Benzoyl urea derivatives that are alpha helical peptides mimetics that mimic BH3-only proteins, compositions containing them, their conjugation to cell-targeting-moieties, and their use in the regulation of cell death are disclosed. The benzoyl urea derivatives are capable of binding to and neutralizing pro-survival Bcl-2 proteins. Use of benzoyl urea derivatives in the treatment and/or prophylaxis of diseases or conditions associated with deregulation of cell death are also described.
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- Therapeutic heterocycles
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A compound having the general formula and methods of using such compounds for the treatment of diseases and pharmaceutical composition comprising such compounds.
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- Mild and regioselective oxidative bromination of anilines using potassium bromide and sodium perborate
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The selective monobromination of various deactivated anilines using potassium bromide and sodium perborate as oxidant has been achieved. The use of ammonium molybdate as catalyst accelerates the rate of reaction but is not essential to obtain good yields and high selectivities. (C) 2000 Elsevier Science Ltd.
- Roche, Didier,Prasad, Kapa,Repic, Oljan,Blacklock, Thomas J.
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p. 2083 - 2085
(2007/10/03)
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- Axially Dissymmetric Bis(triaryl)phosphines in the Biphenyl Series: Synthesis of (6,6'-Dimethylbiphenyl-2,2'-diyl)bis(diphenylphosphine) ('BIPHEMP') and Analogues, and their Use in Rh(I)-Catalyzed Asymmetric Isomerisations of N,N-Diethylnerylamine
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The axially dissymmetric diphosphines (-)-(R)- and (+)-(S)-(6,6'-dimethylbiphenyl-2,2'-diyl)bis(diphenylphosphine)((-)-(R)-10 and (+)-(S)-10; 'BIPHEMP') have been synthesized, starting from (R)- and (S)-6,6'-dimethylbiphenyl-2,2'-diamine ((R)- and (S)-16), respectively, via Sandmeyer reaction, lithiation, and phosphinylation.Moreover, racemic 4,4'-dimethyl- and 4,4'-bis(dimethylamino)-substituted analogues 11 and 12, respsctively, and the 6,6'-bridged analogue 1,11-bis(diphenylphosphino)-5,7-dihydrodibenzoxepin (13) were synthesized and resolved into optically pure (R)- and (S)-enantiomers via complexation with di-μ-chlorobisphenyl-C,N>dipalladium(II) ((R)-18).The molecular structures of the diphosphines (S)-10 and (R)-13 and of two derived cationic Rh(I) complexes, BF4 and BF4 were determined by X-ray analyses.Absolute configurations were established for (+)-(S)-10 by X-ray analyses of both the free diphosphine and of the derived Rh(I) complex, and for (-)-13 by X-ray analysis of the derived Rh(I) complex.Configurational assignments for the substituted BIPHEMP analogues 11 and 12 were achieved by means of 1H-NMR comparisons of the Pd(II) complexes derived from the diphosphines and (R)-18, and by means of CD comparisons.The BIPHEMP ligand 10 and analogues 11, 12, and 13 are the first examples of optically active bis(triarylphosphines) containing the axially dissymmetric biphenyl moiety.All these new diphosphines proved to be excellent asymmetry-inducing ligands in Rh(I)-catalyzed isomerizations of N,N-diethylnerylamine affording citronellal enamine of 98-99percent ee.
- Schmid, Rudolf,Cereghetti, Marco,Heiser, Bernd,Schoenholzer, Peter,Hansen, Hans-Juergen
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p. 897 - 930
(2007/10/02)
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