- Novel Substituted Purine Isosteres: Synthesis, Structure-Activity Relationships and Cytotoxic Activity Evaluation
-
A number of pyrrolo[2,3-c]pyridines, pyrrolo[3,2-d]pyrimidines and pyrazolo[4,3-d]pyrimidines were designed and synthesized as antiproliferative agents. The target compounds possessed selected substituents in analogous positions on the central scaffold th
- Dimitrakis, Spyridon,Gavriil, Efthymios-Spyridon,Gioti, Katerina,Lougiakis, Nikolaos,Marakos, Panagiotis,Pouli, Nicole,Pousias, Athanasios,Tenta, Roxane
-
-
- HETEROCYCLIC PAD4 INHIBITORS
-
The disclosure generally relates to substituted heterocyclic compounds of Formula (Ia), which are inhibitors of PAD4, method for preparing these compounds, pharmaceutical compositions comprising these compounds and use of these compounds in the treatment of a disease or a disorder associated with PAD4 enzyme activity.
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Page/Page column 187
(2021/08/20)
-
- Selective Inhibitors of Helicobacter pylori Methylthioadenosine Nucleosidase and Human Methylthioadenosine Phosphorylase
-
Bacterial 5′-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) hydrolyzes adenine from its substrates to form S-methyl-5-thioribose and S-ribosyl-l-homocysteine. MTANs are involved in quorum sensing, menaquinone synthesis, and 5′-methylthioadenosine recycling to S-adenosylmethionine. Helicobacter pylori uses MTAN in its unusual menaquinone pathway, making H. pylori MTAN a target for antibiotic development. Human 5′-methylthioadenosine phosphorylase (MTAP), a reported anticancer target, catalyzes phosphorolysis of 5′-methylthioadenosine to salvage S-adenosylmethionine. Transition-state analogues designed for HpMTAN and MTAP show significant overlap in specificity. Fifteen unique transition-state analogues are described here and are used to explore inhibitor specificity. Several analogues of HpMTAN bind in the picomolar range while inhibiting human MTAP with orders of magnitude weaker affinity. Structural analysis of HpMTAN shows inhibitors extending through a hydrophobic channel to the protein surface. The more enclosed catalytic sites of human MTAP require the inhibitors to adopt a folded structure, displacing the phosphate nucleophile from the catalytic site.
- Harijan, Rajesh K.,Hoff, Oskar,Ducati, Rodrigo G.,Firestone, Ross S.,Hirsch, Brett M.,Evans, Gary B.,Schramm, Vern L.,Tyler, Peter C.
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supporting information
p. 3286 - 3296
(2019/04/17)
-
- Medicine composition for treating diabetes and nephropathy and preparation method of composition
-
The invention relates to a medicine composition for treating diabetes and nephropathy. The medicine composition comprises a compound or a derivative of the compound which serves as a medicinal composition, a filling agent, a stabilizing agent, a flow agent, a flavoring agent and other additives. The invention further discloses a preparation method of the medicine composition for treating the diabetes and the nephropathy. According to the medicine composition, kidney hypertrophy of diabetes patients is relieved by restraining decrease of MMP-9 in kidney expression and expression of TNF-alpha inkidney, so that the kidney is protected.
- -
-
Paragraph 0009
(2018/10/02)
-
- SELECTIVE INHIBITORS OF CLINICALLY IMPORTANT MUTANTS OF THE EGFR TYROSINE KINASE
-
The present invention provides compounds of Formula (I) or a subgeneric structure or species thereof, or a pharmaceutically acceptable salt, ester, solvate, and/or prodrug thereof, and methods and compositions for treating or ameliorating abnormal cell proliferative disorders, such as cancer, wherein A, R2, R3, R10, E1, E2, E3, Y, and Z are as defined herein.
- -
-
Page/Page column 258
(2017/08/01)
-
- Synthesis and antiproliferative activity of thiazolyl-bis-pyrrolo[2,3-b]pyridines and indolyl-thiazolyl-pyrrolo[2,3-c]pyridines, nortopsentin analogues
-
Two new series of nortopsentin analogues, in which the imidazole ring of the natural product was replaced by thiazole and indole units were both substituted by 7-azaindole moieties or one indole unit was replaced by a 6-azaindole portion, were efficiently synthesized. Compounds belonging to both series inhibited the growth of HCT-116 colorectal cancer cells at low micromolar concentrations, whereas they did not affect the viability of normal-like intestinal cells. A compound of the former series induced apoptosis, evident as externalization of plasma membrane phosphatidylserine (PS), and changes of mitochondrial trans-membrane potential, while blocking the cell cycle in G2/M phase. In contrast, a derivative of the latter series elicited distinct responses in accordance with the dose. Thus, low concentrations (GI30) induced morphological changes characteristic of autophagic death with massive formation of cytoplasmic acid vacuoles without apparent loss of nuclear material, and with arrest of cell cycle at the G1 phase, whereas higher concentrations (GI70) induced apoptosis with arrest of cell cycle at the G1 phase.
- Carbone, Anna,Parrino, Barbara,Vita, Gloria Di,Attanzio, Alessandro,Span, Virginia,Montalbano, Alessandra,Barraja, Paola,Tesoriere, Luisa,Livrea, Maria Antonia,Diana, Patrizia,Cirrincione, Girolamo
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p. 460 - 492
(2015/02/05)
-
- Azaindolylsulfonamides, with a more selective inhibitory effect on histone deacetylase 6 activity, exhibit antitumor activity in colorectal cancer HCT116 cells
-
A series of indolylsulfonylcinnamic hydroxamates has been synthesized. Compound 12, (E)-3-(3-((1H-pyrrolo[2,3-b]pyridin-1-yl)sulfonyl)phenyl)-N- hydroxyacrylamide, which has a 7-azaindole core cap, was shown to have antiproliferative activity against KB, H460, PC3, HSC-3, HONE-1, A549, MCF-7, TSGH, MKN45, HT29, and HCT116 human cancer cell lines. Pharmacological studies indicated that 12 functions as a potent HDAC inhibitor with an IC50 value of 0.1 μM. It is highly selective for histone deacetylase 6 (HDAC6) and is 60-fold more active than against HDAC1 and 223-fold more active than against HDAC2. It has a good pharmacokinetic profile with oral bioavailability of 33%. In in vivo efficacy evaluations in colorectal HCT116 xenografts, compound 12 suppresses tumor growth more effectively than SAHA (1, N-hydroxy-N′- phenyloctanediamide) and is therefore seen as a suitable candidate for further investigation.
- Lee, Hsueh-Yun,Tsai, An-Chi,Chen, Mei-Chuan,Shen, Po-Jung,Cheng, Yun-Ching,Kuo, Ching-Chuan,Pan, Shiow-Lin,Liu, Yi-Min,Liu, Jin-Fen,Yeh, Teng-Kuang,Wang, Jing-Chi,Chang, Chi-Yen,Chang, Jang-Yang,Liou, Jing-Ping
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p. 4009 - 4022
(2014/06/09)
-
- HETEROCYCLIC COMPOUNDS AS PROTEIN KINASE INHIBITORS
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The present invention provides a heterocyclic compound of formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof or a hydrate thereof, wherein A, A′ B, D, R1, R2 and R3 are as defined herein, a pharmaceutical composition comprising a compound of formula (I) as an active ingredient, methods of production, and methods of use thereof. Particularly, the present invention provides a compound of formula (I) useful for treating or preventing a disease, condition or disorder associated with protein kinases, preferably Janus Kinase family.
- -
-
Paragraph 0361
(2014/06/23)
-
- 4-(Benzoimidazol-2-yl)-thiazole Compounds and Related Aza Derivatives
-
The invention relates to compounds of Formula (I) wherein ring A, X, (R1)n, R2, R3, R4, R4′, R5, n, and p are as described in the description; to pharmaceutically acceptable salts thereof, and to the use of such compounds as medicaments, especially as modulators of the CXCR3 receptor.
- -
-
Paragraph 0814
(2015/01/06)
-
- 4-(BENZOIMIDAZOL-2-YL)-THIAZOLE COMPOUNDS AND RELATED AZA DERIVATIVES
-
The invention relates to compounds of Formula (I) wherein ring A, X, (R1)n, R2, R3, R4, R4', R5, n, and p are as described in the description; to pharmaceutically acceptable salts thereof, and to the use of such compounds as medicaments, especially as modulators of the CXCR3 receptor.
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-
Page/Page column 113
(2013/08/15)
-
- HETEROCYCLIC COMPOUNDS AS PROTEIN KINASE INHIBITORS
-
The present invention provides a heterocyclic compound of formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof or a hydrate thereof, wherein A, A' B, D, R1, R2 and R3 are as defined herein, a pharmaceutical composition comprising a compound of formula (I) as an active ingredient, methods of production, and methods of use thereof. Particularly, the present invention provides a compound of formula (I) useful for treating or preventing a disease, condition or disorder associated with protein kinases, preferably Janus Kinase family.
- -
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Page/Page column 59
(2012/12/13)
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- Novel 3-azaindolyl-4-arylmaleimides exhibiting potent antiangiogenic efficacy, protein kinase inhibition, and antiproliferative activity
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Tumor growth and metastasis are highly associated with the overexpression of protein kinases (PKs) regulating cell growth, apoptosis resistance, and prolonged cell survival. This study describes novel azaindolyl-maleimides with significant inhibition of PKs, such as VEGFR, FLT-3, and GSK-3β which are related to carcinogenesis. Furthermore, these compounds exhibit high kinase selectivity and potent inhibition of angiogenesis and cell proliferation, offering versatile options in cancer treatment strategies.
- Ganser, Christopher,Lauermann, Eva,Maderer, Annett,Stauder, Torsten,Kramb, Jan-Peter,Plutizki, Stanislav,Kindler, Thomas,Moehler, Markus,Dannhardt, Gerd
-
p. 9531 - 9540
(2013/01/16)
-
- Novel indole and azaindole (pyrrolopyridine) cannabinoid (CB) receptor agonists: Design, synthesis, structure-activity relationships, physicochemical properties and biological activity
-
The discovery, synthesis and structure-activity relationship (SAR) of a novel series of cannabinoid 1 (CB1) and cannabinoid 2 (CB 2) receptor ligands are reported. Based on the aminoalkylindole class of cannabinoid receptor agonists, a biphenyl moiety was introduced as novel lipophilic indole 3-acyl substituent in 11-16. Furthermore, the 3-carbonyl tether was replaced with a carboxamide linker in 17-20 and the azaindole (pyrrolopyridine) nucleus was designed as indole bioisostere with improved physicochemical properties in 21-25. Through these SAR efforts, several high affinity CB1/CB2 dual cannabinoid receptor ligands were identified. Indole-3-carboxamide 17 displayed single-digit nanomolar affinity and ~80 fold selectivity for CB1 over the CB2 receptor. The azaindoles displayed substantially improved physicochemical properties (lipophilicity; aqueous solubility). Azaindole 21 elicited potent cannabinoid activity. Cannabinoid receptor agonists 17 and 21 potently modulated excitatory synaptic transmission in an acute rat brain slice model of cannabinoid receptor-modulated neurotransmission.
- Blaazer, Antoni R.,Lange, Jos H.M.,Van Der Neut, Martina A.W.,Mulder, Arie,Den Boon, Femke S.,Werkman, Taco R.,Kruse, Chris G.,Wadman, Wytse J.
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experimental part
p. 5086 - 5098
(2011/11/29)
-
- KINASE INHIBITORS AND THEIR USE AS PHARMACEUTICAL AGENTS
-
Described herein are compounds that are inhibitors of one or more protein kinases. Also described are pharmaceutical compositions and medicaments that include the compounds described herein. Also described herein are methods of using such protein kinase inhibitors, alone and in combination with other compounds, for conditions or diseases mediated or dependent upon protein kinases
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Page/Page column 35
(2011/11/06)
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- [4[4-(5-AMINOMETHYL-2-FLUORO-PHENYL)-PIPERIDIN-1-YL]-(1H-PYRROLO-PYRIDIN-YL)-METHANONES AND SYNTHESIS THEREOF
-
The present invention relates herein to compounds and compositions for the treatment and amelioration of inflammatory disease. Specifically the present invention relates to compounds that having a tryptase inhibition activity and the intermediates thereof, pharmaceutical compositions comprising such compounds, and a method of treating subjects suffering from a condition disease or disorder that can be ameliorated by the administration of an inhibitor of tryptase including but not limited to for example asthma and other inflammatory diseases including age-related macular degeneration.
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Page/Page column 54
(2011/07/09)
-
- KINASE INHIBITORS AND THEIR USE AS PHARMACEUTICAL AGENTS
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Described herein are compounds that are inhibitors of one or more protein kinases. Also described are pharmaceutical compositions and medicaments that include the compounds described herein. Also described herein are methods of using such protein kinase inhibitors, alone and in combination with other compounds, for conditions or diseases mediated or dependent upon protein kinases.
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Page/Page column 48
(2010/06/11)
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- NOVEL 6-AZAINDOLE AMINOPYRIMIDINE DERIVATIVES HAVING NIK INHIBITORY ACTIVITY
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The present invention relates to a compound of formula I: wherein: R1 is C1-6 alkyl, C3-8 cycloalkyl, aryl, heterocyclyl, or -COR1x, where the C1-6 alkyl, C3-8 cycloalkyl, aryl, and heterocyclyl may be substituted; and R1x is C3-8 cycloalkyl, aryl, or heterocyclyl, any of which may be substituted; R2, R3, R4, R5, R6, and R7 are each independently hydrogen, halogen, C1-6 alkyl, or aryl, where the C1-6 alkyl or aryl may be substituted; R8 is hydrogen, C1-6 alkyl, aryl, or heterocyclyl, any of which may be substituted; or a pharmaceutically acceptable salt or ester thereof.
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Page/Page column 38; 39
(2010/04/28)
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- Design, synthesis and dopamine D4 receptor binding activities of new N-heteroaromatic 5/6-ring Mannich bases
-
A series of phenylpiperazine-methyl-substituted 1H-pyrrolo[2,3-c]pyridine, imidazo[1,2-c]-, pyrrolo[2,3-d]- and pyrrolo[3,2-d]pyrimidines were prepared as selective dopamine D4-ligands. The pyrrolo[2,3-d]pyrimidine derivatives 12d (Ki = 1,9 nM)
- Linz, Sabine,Mueller, Joerg,Huebner, Harald,Gmeiner, Peter,Troschuetz, Reinhard
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experimental part
p. 4448 - 4458
(2009/12/04)
-
- A palladium-catalyzed alkylation/direct arylation synthesis of nitrogen-containing heterocycles
-
(Chemical Equation Presented) A norbornene-mediated palladium-catalyzed sequence is described in which an alkyl-aryl bond and an aryl-heteroaryl bond are formed in one reaction vessel. The aryl-heteroaryl bond-forming step occurs via a direct arylation re
- Blaszykowski, Christophe,Aktoudianakis, Evangelos,Alberico, Dino,Bressy, Cyril,Hulcoop, David G.,Jafarpour, Farnaz,Joushaghani, Arash,Laleu, Benoit,Lautens, Mark
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p. 1888 - 1897
(2008/09/18)
-
- INHIBITORS OF VEGF RECEPTOR AND HGF RECEPTOR SIGNALING
-
The invention relates to the inhibition of vascular endothelial growth factor (VEGF) receptor signaling and hepatocyte growth factor (HGF) receptor signaling. The invention provides compounds and methods for inhibiting VEGF receptor signaling and HGF receptor signaling. The invention also provides compositions and methods for treating cell proliferative diseases and conditions
- -
-
Page/Page column 199-200
(2010/02/15)
-
- Indole, azaindole and related heterocyclic N-substituted piperazine derivatives
-
This invention provides compounds of Formula I, including pharmaceutically accceptable salts thereof, having drug and bio-affecting properties, their pharmaceutical compositions and method of use. These compounds possess unique antiviral activity, whether used alone or in combination with other antivirals, antiinfectives, immunomodulators or HIV entry inhibitors. More particularly, the present invention relates to the treatment of HIV and AIDS. The compounds of Formula I have the formula wherein: Z is Q is selected from the group consisting of m is 2; A is selected from the group consisting of cinnolinyl, napthyridinyl, quinoxalinyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, azabenzofuryl, and phthalazinyl each of which may be optionally substituted with one or two groups independently selected from methyl, methoxy, hydroxy, amino and halogen; and —W— is
- -
-
-
- Prodrugs of piperazine and substituted piperidine antiviral agents
-
This invention provides for prodrug Compounds I, pharmaceutical compositions thereof, and their use in treating HIV infection. wherein: X is C or N with the proviso that when X is N, R1 does not exist; W is C or N with the proviso that when W is N, R2 does not exist; V is C; E is hydrogen or a pharmaceutically acceptable salt thereof; and Y is selected from the group consisting of Also, this invention provides for intermediate Compounds II useful in making prodrug Compounds I. wherein: L and M are independently selected from the group consisting of C1-C6 alkyl, phenyl, benzyl, trialkylsilyl, -2,2,2-trichloroethoxy and 2-trimethylsilylethoxy.
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-
Page/Page column 24
(2010/02/14)
-
- Composition and antiviral activity of substituted azaindoleoxoacetic piperazine derivatives
-
This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with azaindoleoxoacetyl piperazine derivatives. These compounds possess unique antiviral activity, whether used alone or in combination with other antivirals, antiinfectives, immunomodulators or HIV entry inhibitors. More particularly, the present invention relates to the treatment of HIV and AIDS.
- -
-
-
- Indole, azaindole and related heterocyclic 4-alkenyl piperidine amides
-
This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with new piperidine 4-alkenyl derivatives that possess unique antiviral activity. More particularly, the present invention relates to compounds useful for the treatment of HIV and AIDS. The compounds of the invention for the general Formula I: wherein: Z is Q is selected from the group consisting of: —W— is
- -
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Page/Page column 30
(2010/02/06)
-
- Antiviral azaindole derivatives
-
The present invention is directed to a series of chemical entities that express HIV-1 inhibitory activities.
- -
-
-
- Antiviral azaindole derivatives
-
The present invention is directed to a series of chemical entities that express HIV-1 inhibitory activities.
- -
-
-
- A general method for the preparation of 4-and 6-azaindoles
-
Nitropyridines reacted with an excess of vinyl Grignard reagent to produce 4- or 6-azaindoles. Improved yields were obtained when a halogen atom was present at the position α to the nitrogen atom in the pyridine ring.
- Zhang, Zhongxing,Yang, Zhong,Meanwell, Nicholas A.,Kadow, John F.,Wang, Tao
-
p. 2345 - 2347
(2007/10/03)
-