- Affinity-Based Selectivity Profiling of an In-Class Selective Competitive Inhibitor of Acyl Protein Thioesterase 2
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Activity-based protein profiling (ABPP) has revolutionized the discovery and optimization of active-site ligands across distinct enzyme families, providing a robust platform for in-class selectivity profiling. Nonetheless, this approach is less straightfo
- Won, Sang Joon,Eschweiler, Joseph D.,Majmudar, Jaimeen D.,Chong, Fei San,Hwang, Sin Ye,Ruotolo, Brandon T.,Martin, Brent R.
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- TRUNCATED ITRACONAZOLE ANALOGUES AND METHODS OF USE THEREOF
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Disclosed herein are analogues of itraconazole that are potent hedgehog signaling pathway inhibitors. The compounds are expected to be useful in the treatment of cell proliferation disorders such as cancer, particularly cancers that are dependent upon the hedgehog signaling pathway such as basal cell carcinoma and medulloblastoma.
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Paragraph 0147
(2021/02/19)
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- ADENOSINE A2A RECEPTOR ANTAGONISTS AND USES THEREOF
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Disclosed herein are compounds, compositions, and methods for modulating the A2A2A adenosine receptor with the compounds and compositions disclosed herein. Also described are methods of treating diseases or disorders that are mediated by the A
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Paragraph 00372
(2021/02/12)
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- ADENOSINE RECEPTOR BINDING COMPOUNDS
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The present invention relates to pharmaceutical compounds and compositions of Formula (I) and methods of treatment using the compounds and compositions, especially for the treatment and/or prevention of a proliferation disorder, such as cancer. Compounds of Formula (I) as further described herein are shown modulators of the adenosine A2A receptor and exhibit antiproliferative activity. Accordingly, these compounds are useful to treat proliferative disorders such as cancer, and other adenosine receptor-related conditions including an inflammatory disease, renal disease, diabetes, vascular disease, lung disease, or an autoimmune disease.
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Paragraph 00333
(2020/02/06)
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- Truncated Itraconazole Analogues Exhibiting Potent Anti-Hedgehog Activity and Improved Drug-like Properties
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We conducted a structure-activity relationship study to explore simplified analogues of the itraconazole (ITZ) scaffold for their ability to inhibit the hedgehog (Hh) signaling pathway. These analogues were based on exploring the effects of chemical modifications to the linker and triazolone/side chain region of ITZ. Analogue 11 was identified as the most potent compound in our first generation, with an IC50 value of 81 nM in a murine Hh-dependent basal cell carcinoma. Metabolic identification studies led us to identify truncated piperazine (26) as the major metabolite in human liver microsomes (HLMs) and an improved Hh pathway inhibitor (IC50 = 22 nM). This work verifies that continued truncation of the ITZ scaffold is a practical method to maintain potent anti-Hh activity while also reducing the molecular weight for the ITZ scaffold and achieving improved pharmacokinetic properties.
- Wen, Jiachen,Chennamadhavuni, Divya,Morel, Shana R.,Hadden, M. Kyle
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p. 1290 - 1295
(2019/09/30)
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- Potent human glutaminyl cyclase inhibitors as potential anti-Alzheimer's agents: Structure-activity relationship study of Arg-mimetic region
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Pyroglutamate-modified amyloid β peptides (pGlu-Aβ) are highly neurotoxic and promote the formation of amyloid plaques. The pGlu-Aβ peptides are generated by glutaminyl cyclase (QC), and recent clinical studies indicate that QC represents an alternative t
- Ngo, Van T.H.,Hoang, Van-Hai,Tran, Phuong-Thao,Ann, Jihyae,Cui, Minghua,Park, Gyungseo,Choi, Sun,Lee, Jiyoun,Kim, Hee,Ha, Hee-Jin,Choi, Kwanghyun,Kim, Young-Ho,Lee, Jeewoo
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supporting information
p. 1035 - 1049
(2018/02/12)
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- N/O-LINKED DEGRONS AND DEGRONIMERS FOR PROTEIN DEGRADATION
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This invention provides Degronimers that have E3 Ubiquitin Ligase targeting moieties (Degrons) that can be linked to a targeting ligand for a protein that has been selected for in vivo degradation, and methods of use and compositions thereof as well as methods for their preparation. The invention also provides Degrons that can be used to treat disorders mediated by cereblon or an Ikaros family protein, and methods of use and compositions thereof as well as methods for their preparation.
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Page/Page column 310; 311
(2019/01/10)
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- ANTIMYCOTIC TRIAZOLE COMPOUND
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The invention relates to Compound (I), which is 4-(4-(4-(((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methoxy)phenyl)piperazin-1-yl)-N-(4-fluorophenyl)benzamide, or a pharmaceutically acceptable salt thereof, usefu
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Page/Page column 3; 12
(2017/07/08)
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- A process for the preparation of intermediates [...] and the intermediate
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The invention discloses a preparation method of a vilazodone intermediate and an intermediate. The preparation method of the vilazodone intermediate (5-piperazinylbenzofuran-2-formylimine salts) comprises a step of soaking a compound represented by the formula 7 in a water solution of an inorganic strong acid to carry out hydrolysis deprotection salt-forming reactions, which are represented in the description; wherein the X represents an inorganic strong acid, and the inorganic strong acid can be hydrochloric acid, sulfuric acid, or hydrobromic acid. The invention also discloses a preparation method of a compound represented by the formula 7 and a compound represented by the formula 6. The provided preparation method has the advantages of high yield, easy purification, high purity, and low cost, and is suitable for industrial massive production.
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Paragraph 0054; 0055; 0056
(2016/11/02)
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- Novel bicyclic nitroimidazole carbamate compounds, process for preparation thereof and pharmaceutical composition for preventing or treating tuberculosis containing the same as an active ingredient
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A bicyclic nitroimidazole carbamate compound represented by chemical formula 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition for preventing or treating tuberculosis disease containing the same as an active ingredient. Chemical Formula 1. In Chemical Formula 1, R. 1 And R2 Are as defined in the description of the invention. The bicyclic nitroimidazole carbamate compounds of the present invention exhibit excellent inhibitory effects on vitality and non-active tuberculosis. The compounds can be useful in the treatment of tuberculosis.
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Paragraph 0208-0212
(2021/06/01)
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- Synthesis and Biological Evaluation of Polar Functionalities Containing Nitrodihydroimidazooxazoles as Anti-TB Agents
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Novel polar functionalities containing 6-nitro-2,3-dihydroimidazooxazole (NHIO) analogues were synthesized to produce a compound with enhanced solubility. Polar functionalities including sulfonyl, uridyl, and thiouridyl-bearing NHIO analogues were synthes
- Yempalla, Kushalava Reddy,Munagala, Gurunadham,Singh, Samsher,Kour, Gurleen,Sharma, Shweta,Chib, Reena,Kumar, Sunil,Wazir, Priya,Singh,Raina, Sushil,Bharate, Sonali S,Khan, Inshad Ali,Vishwakarma, Ram A.,Singh, Parvinder Pal
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supporting information
p. 1059 - 1064
(2015/10/20)
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- Assay for the Detection of the Phenylpiperazine Family
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The current invention describes novel immunogens which are used in the production of novel antibodies with unique binding properties in that they cross-react with a variety of phenylpiperazine derivatives. These antibodies enable methods and kits to detec
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Paragraph 0069
(2013/09/12)
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- Assay for the detection of the phenypiperazine family
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The current invention describes novel immunogens which are used in the production of novel antibodies with unique binding properties in that they cross-react with a variety of phenylpiperazine derivatives. These antibodies enable methods and kits to detec
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Paragraph 0052
(2013/09/12)
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- Pyridinylquinazolines selectively inhibit human methionine aminopeptidase-1 in cells
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Methionine aminopeptidases (MetAPs), which remove the initiator methionine from nascent peptides, are essential in all organisms. While MetAP2 has been demonstrated to be a therapeutic target for inhibiting angiogenesis in mammals, MetAP1 seems to be vital for cell proliferation. Our earlier efforts identified two structural classes of human MetAP1 (HsMetAP1)-selective inhibitors (1-4), but all of them failed to inhibit cellular HsMetAP1. Using Mn(II) or Zn(II) to activate HsMetAP1, we found that 1-4 could only effectively inhibit purified HsMetAP1 in the presence of physiologically unachievable concentrations of Co(II). In an effort to seek Co(II)-independent inhibitors, a novel structural class containing a 2-(pyridin-2-yl)quinazoline core has been discovered. Many compounds in this class potently and selectively inhibited HsMetAP1 without Co(II). Subsequently, we demonstrated that 11j, an auxiliary metal-dependent inhibitor, effectively inhibited HsMetAP1 in primary cells. This is the first report that an HsMetAP1-selective inhibitor is effective against its target in cells.
- Zhang, Feiran,Bhat, Shridhar,Gabelli, Sandra B.,Chen, Xiaochun,Miller, Michelle S.,Nacev, Benjamin A.,Cheng, Yim Ling,Meyers, David J.,Tenney, Karen,Shim, Joong Sup,Crews, Phillip,Amzel, L. Mario,Ma, Dawei,Liu, Jun O.
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p. 3996 - 4016
(2013/07/19)
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- Use of small-molecule crystal structures to address solubility in a novel series of g protein coupled receptor 119 agonists: Optimization of a lead and in vivo evaluation
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G protein coupled receptor 119 (GPR119) is viewed as an attractive target for the treatment of type 2 diabetes and other elements of the metabolic syndrome. During a program toward discovering agonists of GPR119, we herein describe optimization of an initial lead compound, 2, into a development candidate, 42. A key challenge in this program of work was the insolubility of the lead compound. Small-molecule crystallography was utilized to understand the intermolecular interactions in the solid state and resulted in a switch from an aryl sulphone to a 3-cyanopyridyl motif. The compound was shown to be effective in wild-type but not knockout animals, confirming that the biological effects were due to GPR119 agonism.
- Scott, James S.,Birch, Alan M.,Brocklehurst, Katy J.,Broo, Anders,Brown, Hayley S.,Butlin, Roger J.,Clarke, David S.,Davidsson, ?jvind,Ertan, Anne,Goldberg, Kristin,Groombridge, Sam D.,Hudson, Julian A.,Laber, David,Leach, Andrew G.,MacFaul, Philip A.,McKerrecher, Darren,Pickup, Adrian,Schofield, Paul,Svensson, Per H.,S?rme, Pernilla,Teague, Joanne
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p. 5361 - 5379
(2012/08/28)
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- FUSED HETEROCYCLIC COMPOUND
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The present invention relates to a fused heterocyclic compound having the Formula 1, which is useful as a platelet aggregation inhibitor, a method for preparing the same, and a pharmaceutical composition for inhibiting platelet aggregation comprising the same.
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Page/Page column 103
(2011/07/29)
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- Gem-bisphosphonate-ended group dendrimers: Design and gadolinium complexing properties
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The synthesis of the first gem-bisphosphonate-ended group dendrimers is described using nucleophilic substitution of terminal P(S)Cl2 units of phosphorus dendrimers of generation 1 to 3 with protected aminophenols followed by deprotection of am
- Franc, Gregory,Turrin, Cedric-Olivier,Cavero, Emma,Costes, Jean-Pierre,Duhayon, Carine,Caminade, Anne-Marie,Majoral, Jean-Pierre
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experimental part
p. 4290 - 4299
(2011/02/24)
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- Synthesis of novel WAY 100635 derivatives containing a norbornene group and radiofluorination of [18F]AH1.MZ as a serotonin 5-HT1A receptor antagonist for molecular imaging
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5-HT1A receptors are involved in a variety of psychiatric disorders and in vivo molecular imaging of the 5-HT1A status represents an important approach to analyze and treat these disorders. We report herein the synthesis of three new
- Herth, Matthias M.,Kramer, Vasko,Roesch, Frank
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experimental part
p. 201 - 207
(2010/06/14)
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- LIGANDS FOR IMAGING CARDIAC INNERVATION
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Novel compounds that find use as imaging agents within nuclear medicine applications (PET imaging) for imaging of cardiac innervation are disclosed. These PET based radiotracers may exhibit increased stability, decreased NE release (thereby reducing side
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Page/Page column 51
(2008/12/07)
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- 2-AMINO-4-HYDROXY-5-PYRIMIDINECARBOXAMIDE DERIVATIVES AND RELATED COMPOUNDS AS INHIBITORS OF T CELL ACTIVATION FOR THE TREATMENT OF INFLAMMATORY DISEASES
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The present invention relates to pyrimidine or pyridine carboxamides or pharmaceutically-acceptable salts thereof. Also included is a method of treatment of inflammation, inhibition of T cell activation and proliferation, arthritis, rheumatoid arthritis,
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Page/Page column 78
(2008/06/13)
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- SUBSTITUTED PIPERAZINES, (1,4) DIASZEPINES, AND 2,5-DIAZABICYCLO (2.2.1) HEPTANES AS HISTAMINE H1 AND/OR H3 ANTAGONISTS OR HISTAMINE H3 REVERSE ANTAGONISTS
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The present invention relates to novel piperazine and azepine derivatives having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of neurodegenerative disorders including Alzheimer's disease.
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- Palladium/proazaphosphatrane-catalyzed amination of aryl halides possessing a phenol, alcohol, acetanilide, amide or an enolizable ketone functional group: Efficacy of lithium bis(trimethylsilyl)amide as the base
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A commercially available catalyst system comprising Pd(OAc)2 or Pd2(dba)3 and the proazaphosphatrane ancillary ligand P(i-BuNCH2CH2)3N (1) for the amination of aryl halides substituted with a phenol, alcohol, acetanilide, amide or ketone group containing an enolizable hydrogen is described. The reaction is performed in the presence of LiN(SiMe3)2 as the base. Other bases tested were either less effective or completely non-functional.
- Urgaonkar, Sameer,Verkade, John G.
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p. 611 - 616
(2007/10/03)
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- AROMATIC AMINE DERIVATIVES, PROCESS FOR THE PREPARATION THEREOF AND AGENTS CONTAINING THE SAME
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Compounds of a formula: wherein Ring A represents an optionally-substituted aromatic ring; Ring B represents an optionally-substituted cyclic hydrocarbon group; Z represents an optionally-substituted cyclic group; R1 represents a hydrogen atom, an optionally-substituted hydrocarbon group, an optionally-substituted heterocyclic group, or an acyl group; R2 represents an optionally-substituted amino group; D represents a chemical bond or a divalent group; E represents -CO-, -CON(Ra)-, COO-, -N(Ra)CON(Rb)-, -N(Ra)COO-, -N(Ra)SO2-, -N(Ra)-, -O-, -S-,-SO- or -SO2- (in which Ra and Rb each independently represent a hydrogen atom or an optionally-substituted hydrocarbon group); G represents a chemical bond or a divalent group; L represents (1) a chemical bond or (2) a divalent hydrocarbon group optionally having from 1 to 5 substituents selected from;(i) a C1-6 alkyl group,(ii) a halogeno-C1-6 alkyl group,(iii) a phenyl group,(iv) a benzyl group,(v) an optionally-substituted amino group,(vi) an optionally-substituted hydroxy group, and(vii) a carbamoyl or thiocarbamoyl group optionally substituted by: a C1-6 alkyl group, an optionally-substituted phenyl group, or an optionally-substituted heterocyclic group, and optionally interrupted by -O- or -S-; X represents an oxygen atom, an optionally-oxidized sulfur atom, an optionally-substituted nitrogen atom, or an optionally-substituted divalent hydrocarbon group; Y represents two hydrogen atoms, an oxygen atom or a sulfur atom; .... means that R2 may be bonded to the atom on Ring B to form a ring, or their salts, and a method for producing them.
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- Heterocyclic compounds for the treatment of CNS and cardiovascular disorders
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Novel aromatic bicyclic amines of formula (I) STR1 are useful in treating central nervous system disorders and cardiac arrhythmias and cardiac fibrillation.
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- Carboxylic acid derivatives, medicaments comprising these compounds, their use and processes for their production
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The present invention relates to carboxylic acid derivatives of the general formula STR1 in which Ra to Rc, A, B, D, E and X1 to X3 are as defined in claim 1, their tautomers, their stereoisomers including their mixtures, and their salts, in particular their physiologically tolerated salts with inorganic or organic acids or bases, which have useful pharmacological properties, preferably aggregation-inhibiting inhibiting actions, medicaments containing these compounds, their use and processes for their preparation.
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- Pyrrolo-pyridine derivatives
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A class of pyrrolo[2,3-b]pyridine derivatives, substituted at the 3-position by a substituted piperazinylmethyl moiety, are antagonists of dopamine receptor subtypes within the brain, having a selective affinity for the dopamine D 4 receptor subtype over other dopamine receptor subtypes, and are accordingly of benefit in the treatment and/or prevention of psychotic disorders such as schizophrenia while manifesting fewer side-effects than those associated with classical neuroleptic drugs.
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