- Design, synthesis and biological evaluation of low molecular weight CXCR4 ligands
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The chemokine receptor CXCR4/stromal cell-derived factor-1 (SDF-1: CXCL12) signaling axis represents a crucial drug target due to its relevance to several diseases such as HIV-1 infection, cancer, leukemia, and rheumatoid arthritis. With the aim of enhancing the binding affinity and anti-HIV activity of a potent CXCR4 ligand as a lead, 23 low molecular weight compounds containing dipicolylamine (Dpa) and cyclam cationic moieties with varying spacers and spatial positioning were designed, synthesized and biologically evaluated. All of the synthesized compounds screened at 1.0 μM in the NanoBRET assay system exhibited >70% inhibition of the binding of a competitive probe TAMRA-Ac-TZ14011 (10 nM) to CXCR4 in the presence of zinc (II) ion. Furthermore, selected compounds 3, 8, 9, 19 and 21 with spatial distances between the next carbon to Dpa and the next carbon to cyclam within the range of 6.5–7.5 ? showed potent binding affinity selective for CXCR4 with IC50 values of 1.6, 7.9, 5.7, 3.5 and 4.5 nM, respectively, with corresponding high anti-HIV activity with EC50s of 28, 13, 21, 28 and 61 nM, respectively, in the presence of zinc (II) ion. Some compounds with remarkably more potent CXCR4-binding affinity than that of an initial lead were obtained. These compounds interact with different but overlapping amino acid residues of CXCR4. The present studies have developed new low molecular weight CXCR4 ligands with high CXCR4-binding and anti-HIV activities, which open avenue into the development of more potent CXCR4 ligands.
- Sakyiamah, Maxwell M.,Kobayakawa, Takuya,Fujino, Masayuki,Konno, Makoto,Narumi, Tetsuo,Tanaka, Tomohiro,Nomura, Wataru,Yamamoto, Naoki,Murakami, Tsutomu,Tamamura, Hirokazu
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supporting information
p. 1130 - 1138
(2019/02/16)
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- PYRUVATE KINASE ACTIVATORS FOR USE IN TREATING BLOOD DISORDERS
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Described herein are compounds that activate pyruvate kinase R, pharmaceutical compositions and methods of use thereof. These compounds are represented by Formula (I): Formula (I) wherein R', R2, L', and L2 are as defined herein.
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Page/Page column 157
(2019/03/05)
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- Antibacterial Compounds
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The present invention provides a compound of the following formula, salts, racemates, diastereomers, enantiomers, esters, carbamates, phosphates, sulfates, deuterated forms and prodrugs thereof. Also provided is the use of these compounds as antibacterials, compositions comprising them and processes for their manufacture.
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- HETEROCYCLICALLY SUBSTITUTED ARYL COMPOUNDS AS HIF INHIBITORS
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The present application relates to novel aryl compounds with heterocyclic substituents, processes for their preparation, their use for treatment and/or prevention of diseases and their use for the preparation of medicaments for treatment and/or prevention
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Paragraph 1413; 1414; 1415; 1416; 1417
(2013/08/14)
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- HETEROAROMATIC COMPOUNDS FOR USE AS HIF INHIBITORS
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The present application relates to novel substituted aryl compounds, processes for their preparation, their use for treatment and/or prevention of diseases and their use for the preparation of medicaments for treatment and/or prevention of diseases, in particular for treatment and/or prevention of hyperproliferative and angiogenic diseases and those diseases which arise from metabolic adaptation to hypoxic states. Such treatments can be carried out as monotherapy or also in combination with other medicaments or further therapeutic measures.
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Page/Page column 64
(2011/12/14)
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- 4-Anilino-7-pyridyl-3-quinolinecarbonitriles as Src kinase inhibitors
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A series of 4-anilino-7-pyridyl-3-quinolinecarbonitriles was prepared as Src kinase inhibitors. A systematic SAR study of substitutions on both the pyridine ring and the 3-quinolinecarbonitrile core established the requirements for optimal activity. The l
- Zhang, Nan,Wu, Biqi,Boschelli, Diane H.,Golas, Jennifer M.,Boschelli, Frank
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scheme or table
p. 5071 - 5074
(2010/03/24)
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- Novel cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors
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The present invention relates to a cyclic urea compound of formula I: as defined herein. The invention is also directed to the process for its preparation, pharmaceutical composition comprising it and its pharmaceutical use, as an inhibitor on a protein kinase. Thus, it is useful for preventing or treating a physiological disorder capable of being modulated by inhibiting the activity of a protein kinase, such as a solid tumor.
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- 1-(4-PIPERIDINYL) BENZIMIDAZOLONES AS HISTAMINE H3 ANTAGONISTS
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Disclosed are histamine H3 antagonists of the formula (I) wherein R1 is benzimidazolone derivative, M1 and M2 are optionally substituted carbon or nitrogen, R2 includes optionally substituted aryl or heteroaryl, and the remaining variables are as defined
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- Chemical compounds
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The invention relates to quinazoline derivatives of the formula: [wherein: Y1represents —O—, —S—, —CH2—, —SO—, —SO2—, —NR5CO—, —CONR6—, —SO2NR7—, —NR8SO2— or —NR9— (wherein R5, R6, R8and R9each independently represents hydrogen, alkyl or alkoxyalkyl); R1represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, alkyl, alkoxy, alkylthio, amino or alkylamino. R2represents hydrogen, hydroxy, halogeno, alkyl, alkoxy, trifluoromethyl, cyano, amino or nitro; m is an integer from 1 to 5; R3represents hydroxy, halogeno, alkyl, alkoxy, alkanoyloxy, trifluoromethyl, cyano, amino or nitro; R4represents a group which is or which contains an optionally substituted pyridone, phenyl or aromatic heterocyclic group] and salts thereof; processes for their preparation and pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof as active ingredient. The compounds of formula I and the pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.
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- Inhibitors of prenyl-protein transferase
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The present invention is directed to compounds which inhibit prenyl-protein transferase (FTase) and the prenylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting prenyl-protein transferase and the prenylation of the oncogene protein Ras.
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