797027-83-9Relevant articles and documents
Structure Kinetics Relationships and Molecular Dynamics Show Crucial Role for Heterocycle Leaving Group in Irreversible Diacylglycerol Lipase Inhibitors
Janssen, Antonius P.A.,Van Hengst, Jacob M.A.,Béquignon, Olivier J.M.,Deng, Hui,Van Westen, Gerard J.P.,Van Der Stelt, Mario
, p. 7910 - 7922 (2019/10/11)
Drug discovery programs of covalent irreversible, mechanism-based enzyme inhibitors often focus on optimization of potency as determined by IC50-values in biochemical assays. These assays do not allow the characterization of the binding activity (Ki) and reactivity (kinact) as individual kinetic parameters of the covalent inhibitors. Here, we report the development of a kinetic substrate assay to study the influence of the acidity (pKa) of heterocyclic leaving group of triazole urea derivatives as diacylglycerol lipase (DAGL)-α inhibitors. Surprisingly, we found that the reactivity of the inhibitors did not correlate with the pKa of the leaving group, whereas the position of the nitrogen atoms in the heterocyclic core determined to a large extent the binding activity of the inhibitor. This finding was confirmed and clarified by molecular dynamics simulations on the covalently bound Michaelis-Menten complex. A deeper understanding of the binding properties of covalent serine hydrolase inhibitors is expected to aid in the discovery and development of more selective covalent inhibitors.
Oxidation of imidazole- and pyrazole-derived aldehydes by plant aldehyde dehydrogenases from the family 2 and 10
Fr?mmel, Jan,Kon?itíková, Radka,Kope?ny, David,Soural, Miroslav,?ebela, Marek
, p. 194 - 201 (2019/03/06)
Plant cytosolic aldehyde dehydrogenases from family 2 (ALDH2s, EC 1.2.1.3) are non-specific enzymes and participate for example in the metabolism of acetaldehyde or biosynthesis of phenylpropanoids. Plant aminoaldehyde dehydrogenases (AMADHs, ALDH10 family, EC 1.2.1.19) are broadly specific and play an important role in polyamine degradation or production of osmoprotectants. We have tested imidazole and pyrazole carbaldehydes and their alkyl-, allyl-, benzyl-, phenyl-, pyrimidinyl- or thienyl-derivatives as possible substrates of plant ALDH2 and ALDH10 enzymes. Imidazole represents a building block of histidine, histamine as well as certain alkaloids. It also appears in synthetic pharmaceuticals such as imidazole antifungals. Biological compounds containing pyrazole are rare (e.g. pyrazole-1-alanine and pyrazofurin antibiotics) but the ring is often found as a constituent of many synthetic drugs and pesticides. The aim was to evaluate whether aldehyde compounds based on azole heterocycles are oxidized by the enzymes, which would further support their expected role as detoxifying aldehyde scavengers. The analyzed imidazole and pyrazole carbaldehydes were only slowly converted by ALDH10s but well oxidized by cytosolic maize ALDH2 isoforms (particularly by ALDH2C1). In the latter case, the respective Km values were in the range of 10–2000 μmol l?1; the kcat values appeared mostly between 0.1 and 1.0 s?1. The carbaldehyde group at the position 4 of imidazole was oxidized faster than that at the position 2. Such a difference was not observed for pyrazole carbaldehydes. Aldehydes with an aromatic substituent on their heterocyclic ring were oxidized faster than those with an aliphatic substituent. The most efficient of the tested substrates were comparable to benzaldehyde and p-anisaldehyde known as the best aromatic aldehyde substrates of plant cytosolic ALDH2s in vitro.
Optimization and biological evaluation of 2-aminobenzothiazole derivatives as Aurora B kinase inhibitors
Lee, Eun,An, Ying,Kwon, Junhee,Kim, Keun Il,Jeon, Raok
, p. 3614 - 3622 (2017/06/13)
A strong relationship between abnormal functions of Aurora kinases and tumorigenesis has been reported for decades. Consequently, Aurora kinases serve as potential targets for anticancer agents. Here, we identified aminobenzothiazole derivatives as novel inhibitors of Aurora B kinase through bioisosteric replacement of the previous inhibitors, aminobenzoxazole derivatives. Most of the urea-linked aminobenzothiazole derivatives showed potent and selective inhibitory activity against Aurora B kinase over Aurora A kinase. Molecular modeling indicated that compound 15g bound well to the active site of Aurora B kinase and formed the essential hydrogen bonds. The potent compounds, 15g and 15k, were selected, and their biological effects were evaluated using HeLa cell lines. It was found that these compounds inhibited the phosphorylation of histone H3 at Ser10 and induced G2/M cell cycle arrest. We suggest that the reported compounds have the potential to be further developed as anticancer therapeutics.
Synthesis and evaluation of the 2-aminothiazoles as anti-tubercular agents
Kesicki, Edward A.,Bailey, Mai A.,Ovechkina, Yulia,Early, Julie V.,Alling, Torey,Bowman, Julie,Zuniga, Edison S.,Dalai, Suryakanta,Kumar, Naresh,Masquelin, Thierry,Hipskind, Philip A.,Odingo, Joshua O.,Parish, Tanya
, (2016/06/01)
The 2-aminothiazole series has anti-bacterial activity against the important global pathogen Mycobacterium tuberculosis. We explored the nature of the activity by designing and synthesizing a large number of analogs and testing these for activity against M. tuberculosis, as well as eukaryotic cells. We determined that the C-2 position of the thiazole can accommodate a range of lipophilic substitutions, while both the C-4 position and the thiazole core are sensitive to change. The series has good activity against M. tuberculosis growth with sub-micromolar minimum inhibitory concentrations being achieved. A representative analog was selective for mycobacterial species over other bacteria and was rapidly bactericidal against replicating M. tuberculosis. The mode of action does not appear to involve iron chelation. We conclude that this series has potential for further development as novel antitubercular agents.
ANDROGEN RECEPTOR MODULATING CARBOXAMIDES
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Page/Page column, (2015/05/06)
Compounds of formula (I) or (II) wherein Rx, Rz, R9, R10, R14, R14′, R15, R15′, A and B are as defined in the claims and pharmaceutically acceptable salts and esters thereof, are disclosed. The compounds possess utility as tissue-selective androgen receptor modulators (SARM) and are useful as medicaments in the treatment of prostate cancer and other AR dependent conditions and diseases where AR antagonism is desired.
Pyrazole-3/5-carboxylic acids from 3/5-trifluoromethyl NH-pyrazoles
Ermolenko, Mikhail S.,Guillou, Sandrine,Janin, Yves L.
, p. 257 - 263 (2013/01/15)
We report here the transformation of 3/5-trifluoromethylpyrazoles derivative into the corresponding NH-pyrazole-3/5-carboxylic acids. Moreover, from 4- or 5-iodinated-3/5-trifluoromethylpyrazoles building blocks and the use of Suzuki-Miyaura or Negishi reactions followed by the trifluoromethyl hydrolysis, we illustrate short and original accesses to many series of NH-pyrazole-3/5-carboxylic acids otherwise difficult to prepare.
4,7-DIHYDRO-PYRAZOLO[1,5-a]PYRAZIN-6-YLAMINE DERIVATIVES USEFUL AS INHIBITORS OF BETA-SECRETASE (BACE)
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Paragraph 0099; 0100, (2013/07/31)
The present invention relates to novel 4,7-dihydro-pyrazolo[1,5-a]pyrazin-6-yl-amine derivatives as inhibitors of beta-secretase, also known as beta-site amyloid cleaving enzyme, BACE, BACE1, Asp2, or memapsin2. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which beta-secretase is involved, such as Alzheimer's disease (AD), mild cognitive impairment, senility, dementia, dementia with Lewy bodies, Down's syndrome, dementia associated with stroke, dementia associated with Parkinson's disease or dementia associated with beta-amyloid.
Preparations of 4-substituted 3-carboxypyrazoles
Janin, Yves L.
, p. 1410 - 1414 (2014/01/06)
The scopes of three synthetic methods reported for the preparation of an array of 3-pyrazolecarboxylates featuring substituents on position 4 were investigated. The first one is based on the potassium permanganate oxidation of methylpyrazoles. The second starts with the condensation between DMF dimethylacetal and ethyl pyruvate and is followed by the addition of hydrazine hydrochloride. The last one makes use of the cycloaddition of diazomethane on acrylate esters followed by a bromine-based oxidative rearrangement into 4-substituted 3-pyrazole esters.
4,7-DIHYDRO-PYRAZOLO[1,5-a]PYRAZIN-6-YLAMINE DERIVATIVES USEFUL AS INHIBITORS OF BETA-SECRETASE (BACE)
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Page/Page column 32, (2012/04/10)
The present invention relates to novel 4,7-dihydro-pyrazolo[1,5-a]pyrazin-6-yl- aminederivativesas inhibitors of beta-secretase, also known as beta-site amyloid cleaving enzyme, BACE, BACE1, Asp2, or memapsin2. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which beta-secretaseis involved, such as Alzheimer's disease (AD), mild cognitive impairment, senility, dementia, dementia with Lewy bodies, Down's syndrome, dementia associatedwith stroke, dementia associated with Parkinson's disease or dementia associated with beta- amyloid.
ANDROGEN RECEPTOR MODULATING CARBOXAMIDES
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Page/Page column 62, (2012/11/07)
Compounds of formula (I) wherein Rx, Rz, R9, R10, R14, R14', R15, R15', A and B are as defined in the claims and pharmaceutically acceptable salts and esters thereof, are disclosed. The compounds possess utility as tissue-selective androgen receptor modulators (SARM) and are particularly useful as medicaments in the treatment of prostate cancer and other AR dependent conditions and diseases where AR antagonism is desired.
