- The face selectivity of 1,3-dipolar cycloaddition reactions of 4-butyloxycarbonyl-3,4,5,6-tetrahydropyridine 1-oxide
-
A study of the stereo- and face selectivity of the cycloaddition reactions of a series of mono- and disubstituted alkenes with 4-butyloxycarbonyl-3,4,5,6-tetrahydropyridine 1-oxide has been carried out. Rate constants for the cycloaddition of the nitrone
- Alsbaiee, Alaaeddin,Ali, Shaikh A.
-
-
Read Online
- Beyond Basicity: Discovery of Nonbasic DENV-2 Protease Inhibitors with Potent Activity in Cell Culture
-
The viral serine protease NS2B-NS3 is one of the promising targets for drug discovery against dengue virus and other flaviviruses. The molecular recognition preferences of the protease favor basic, positively charged moieties as substrates and inhibitors, which leads to pharmacokinetic liabilities and off-target interactions with host proteases such as thrombin. We here present the results of efforts that were aimed specifically at the discovery and development of noncharged, small-molecular inhibitors of the flaviviral proteases. A key factor in the discovery of these compounds was a cellular reporter gene assay for the dengue protease, the DENV2proHeLa system. Extensive structure-activity relationship explorations resulted in novel benzamide derivatives with submicromolar activities in viral replication assays (EC50 0.24 μM), selectivity against off-target proteases, and negligible cytotoxicity. This structural class has increased drug-likeness compared to most of the previously published active-site-directed flaviviral protease inhibitors and includes promising candidates for further preclinical development.
- Kühl, Nikos,Leuthold, Mila M.,Behnam, Mira A. M.,Klein, Christian D.
-
supporting information
p. 4567 - 4587
(2021/05/06)
-
- Design, synthesis and anticancer activities of novel dual poly(ADP-ribose) polymerase-1/histone deacetylase-1 inhibitors
-
Currently, synergistic inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) and histone deacetylases (HDACs) has been a potential effective strategy for cancer treatment. Herein, by combining critical pharmacophores in approved drugs olaparib and chidamid
- Liao, Chenzhong,Tian, Yongbin,Xie, Zhouling
-
supporting information
(2020/02/27)
-
- Design and Synthesis of 56 Shape-Diverse 3D Fragments
-
Fragment-based drug discovery is now widely adopted for lead generation in the pharmaceutical industry. However, fragment screening collections are often predominantly populated with flat, 2D molecules. Herein, we describe a workflow for the design and synthesis of 56 3D disubstituted pyrrolidine and piperidine fragments that occupy under-represented areas of fragment space (as demonstrated by a principal moments of inertia (PMI) analysis). A key, and unique, underpinning design feature of this fragment collection is that assessment of fragment shape and conformational diversity (by considering conformations up to 1.5 kcal mol?1 above the energy of the global minimum energy conformer) is carried out prior to synthesis and is also used to select targets for synthesis. The 3D fragments were designed to contain suitable synthetic handles for future fragment elaboration. Finally, by comparing our 3D fragments with six commercial libraries, it is clear that our collection has high three-dimensionality and shape diversity.
- Atobe, Masakazu,Blakemore, David C.,Bond, Paul S.,Chan, Ngai S.,De Fusco, Claudia,Downes, Thomas D.,Firth, James D.,Hubbard, Roderick E.,Jones, S. Paul,Klein, Hanna F.,O'Brien, Peter,Roughley, Stephen D.,Vidler, Lewis R.,Waddelove, Laura,Whatton, Maria Ann,Wheldon, Mary C.,Woolford, Alison J.-A.,Wrigley, Gail L.
-
supporting information
(2020/07/13)
-
- INHIBITORS OF RENAL OUTER MEDULLARY POTASSIUM CHANNEL
-
Compounds of Formula I and the pharmaceutically acceptable salts thereof are provided as inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and chronic kidney disease and conditions associated with excessive salt and water retention.
- -
-
Page/Page column 39
(2016/02/05)
-
- INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
-
The present invention provides compounds of Formula I and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and chronic kidney disease and conditions associated with excessive salt and water retention.
- -
-
Page/Page column 33
(2016/03/13)
-
- INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
-
The present invention provides compounds of Formula I and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and chronic kidney disease and conditions associated with excessive salt and water retention.
- -
-
Page/Page column 49
(2016/05/19)
-
- INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
-
The present invention provides compounds of Formula I (I) and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and chronic kidney disease and conditions associated with excessive salt and water retention.
- -
-
Page/Page column 42
(2016/08/23)
-
- INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
-
The present invention provides compounds of Formula (I) and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir11) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and chronic kidney disease and conditions associated with excessive salt and water retention.
- -
-
Page/Page column 44
(2014/10/04)
-
- Ceric ammonium nitrate-mediated detritylation of tritylated amines
-
Efficient deprotection of tritylated amines to the corresponding amines mediated by 20 mol % ceric ammonium nitrate [Ce(NH4) 2(NO3)6, CAN], 10 equiv of acetic acid and 15 equiv of water in dichloromethane is presented. This method equally worked well in the case of morpholino nucleosides.
- Pattanayak, Sankha,Sinha, Surajit
-
experimental part
p. 34 - 37
(2011/02/25)
-
- OXAZOLE PYRIDINE DERIVATIVES USEFUL AS S1P1 RECEPTOR AGONISTS
-
The present invention provides oxadiazole pyridine derivatives of Formula (I), their use as medicaments and their use for treating multiple sclerosis and other diseases
- -
-
Page/Page column 143
(2010/09/18)
-
- Efficient synthesis and identification of novel propane-1,3-diamino bridged CCR5 antagonists with variation on the basic center carrier
-
By employing pharmacophore-based design and the privileged fragments reassembly, a series of piperidine-/tropane-/piperazine-bridged CCR5 antagonists were designed and synthesized via an efficient convergent synthesis strategy, with focus on the optimal choice of the basic center carrier structure. Significantly, the 4-amino-4-methylpiperidine bridged 1-acyl-1,3-propanediamine compounds were identified as a new class of nanomolar CCR5 antagonists, providing an efficient approach and novel scaffolds for further development of potent CCR5 inhibitors.
- Fan, Xing,Zhang, Hu-Shan,Chen, Li,Long, Ya-Qiu
-
scheme or table
p. 2827 - 2840
(2010/08/22)
-
- Continuous flow hydrogenation of functionalized pyridines
-
The heterogeneous hydrogenation of substituted pyridines has been accomplished by employing a continuous flow hydrogenation device that incorporates in situ hydrogen generation by electrolysis of H20 and pre-packed catalyst cartridges. In general, the hydrogenation reactions proceeded smoothly regardless of the supported precious metal catalyst (Pd/C, Pt/C, or Rh/C). By using 30-80 bar of hydrogen pressure at 60-80 °C full conversion was typically achieved in all cases at a flow rate of 0.5 mL min -1, providing the corresponding piperidines in high yields. For disubstituted pyr idines, variations in stereoselectivity were observed depending on both the metal catalyst and the temperature/ pressure of the hydrogenation reaction. For ethyl nicotinate the selectivity between partial and full hydrogenation could be tuned depending on the hydrogen pressure, solvent, and the choice of supported metal catalyst. Changing the hydrogen source from H20 to D2C) allowed the preparation of de-uteriated derivatives. Wiley-VCH Verlag GmbH & Co. KGaA.
- Irfan, Muhammed,Petricci, Elena,Glasnov, Toma N.,Taddei, Maurizio,Kappe, C. Oliver
-
experimental part
p. 1327 - 1334
(2009/07/19)
-
- Cell-permeable esters of diazeniumdiolate-based nitric oxide prodrugs
-
(Chemical Equation Presented) Although 02-(2,4-dinitrophenyl) derivatives of diazeniumdiolate-based nitric oxide (NO) prodrugs bearing a free carboxylic acid group were activated by glutathione to release NO, these compounds were poor sources of intracellular NO and showed diminished antiproliferative activity against human leukemia HL-60 cells. The carboxylic acid esters of these prodrugs, however, were found to be superior sources of intracellular NO and potent inhibitors of HL-60 cell proliferation.
- Chakrapani, Harinath,Maciag, Anna E.,Citro, Michael L.,Keefer, Larry K.,Saavedra, Joseph E.
-
supporting information; experimental part
p. 5155 - 5158
(2009/06/06)
-
- Antitumor agents 253. Design, synthesis, and antitumor evaluation of novel 9-substituted phenanthrene-based tylophorine derivatives as potential anticancer agents
-
C9-Substituted phenanthrene-based tylophorine derivatives (PBTs) (13-36) were synthesized and evaluated as in vitro anticancer agents against the human A549 lung cancer cell line. Twelve active compounds were further examined against DU-145 (prostate), ZR-751 (breast), KB (nasopharyngeal), and KB-Vin (multidrug resistant KB subline) human cancer cell lines. They showed potent cytotoxic activity against both wild type and matched multidrug resistant KB cell lines, and displayed notable selectivity toward DU-145 (prostate) and ZR-751 (breast) cancer cell lines. The mode of action of this class may be distinctly different from that of other cancer chemotherapeutic compounds. Three PBT analogs were also evaluated in a murine model. Compound 24b showed modest in vivo antitumor activity against human A549 xenograft in nude mice as well as potent in vitro cytotoxic activity, and thus, is a promising anticancer lead compound.
- Wei, Linyi,Shi, Qian,Bastow, Kenneth F.,Brossi, Arnold,Morris-Natschke, Susan L.,Nakagawa-Goto, Kyoko,Wu, Tian-Shung,Pan, Shiow-Lin,Teng, Che-Ming,Lee, Kuo-Hsiung
-
p. 3674 - 3680
(2008/02/10)
-
- PYRROLOPYRIDINE-2-CARBOXYLIC ACID AMIDE INHIBITORS OF GLYCOGEN PHOSHORYLASE
-
Compounds represented by Formula (I): or pharmaceutically acceptable salts thereof, are inhibitors of glycogen phosphorylase and are useful in the prophylactic or therapeutic treatment of diabetes, hyperglycemia, hypercholesterolemia, hyperinsulinemia, hyperlipidemia, hypertension, atherosclerosis or tissue ischemia e.g. myocardial ischemia, and as cardioprotectants.
- -
-
-
- Ceric ammonium nitrate (CAN) mediated esterification of N-Boc amino acids allows either retention or removal of the N-Boc group
-
Reaction of N-Boc amino acids with ceric ammonium nitrate in an alcohol as the solvent at room temperature resulted in the esterification of N-Boc amino acids with Boc group retention. When the reaction was conducted at reflux temperature, esterification was accompanied with simultaneous removal of the Boc group. Both reactions gave the desired products in good yields.
- Kuttan, Ashani,Nowshudin, Shiek,Rao
-
p. 2663 - 2665
(2007/10/03)
-
- Selection of enantioselective acyl transfer catalysts from a pooled peptide library through a fluorescence-based activity assay: An approach to kinetic resolution of secondary alcohols of broad structural scope
-
An assay employing a fluorescently labeled split and pool peptide library has been applied to the discovery of a new class of octapeptide catalysts for the kinetic resolution of secondary alcohols. A highly diverse library of peptide-based catalysts was synthesized on solid-phase synthesis beads such that each individual bead was co-functionalized with (i) a uniform loading of a pH-sensitive fluorophore and (ii) a unique peptidebased catalyst. The library was then screened for activity in acylation reactions employing (±)-sec-phenylethanol as the substrate and acetic anhydride as the acylation agent. From the most active catalysts, a lead peptide (4) was identified that provides a selectivity-factor (krel) of 8.2 upon resynthesis and evaluation under homogeneous conditions. A "directed" second-generation split and pool peptide library was synthesized such that the new peptide sequences in the library were biased toward the lead structure. Random samples of the second generation library were screened in single bead assays that revealed several new peptide-based catalysts that afford improved selectivities in kinetic resolutions. Peptide catalyst 13 proves effective for the kinetic resolution of sec-phenylethanol (krel = 20), as well as eight other secondary alcohols of a broad substrate scope (krel = 4 to > 50).
- Copeland,Miller
-
p. 6496 - 6502
(2007/10/03)
-
- Synthesis and SAR studies of 1-substituted-n-(4-alkoxycarbonylpiperidin-1-yl)alkanes as potent antiarrhythmic agents
-
Synthesis and SAR studies of the title compounds have resulted in the identification of structural and physicochemical parameter (Vw) contributing for antiarrhythmic activity. Among the two most promising compounds 3a and 3b, the 3a has shown antiarrhythmic activity comparable to quinidine.
- Tripathi, Ravish C.,Pandey, Suresh K.,Kar,Dikshit,Saxena, Anil K.
-
p. 2693 - 2698
(2007/10/03)
-
- ANTIALLERGIC COMPOUNDS
-
The present invention is directed to a new class of piperidinyl benzimidazoles that are useful in the treatment of allergic disorders.
- -
-
-
- FeCl3-catalyzed conjugate addition of secondary amines, imidazole and pyrazole to methyl-2-acetamidoacrylate. Preparation of β-dialkylamino-α-alanine and β-(N-heteroaryl)-α-alanine derivatives
-
β-Dialkylamino-α-alanine and β-(N-heteroaryl)-α-alanine derivatives are obtained by conjugate addition of nitrogen based nucleophiles (cyclic and acyclic secondary amines, imidazole and pirazole) to methyl 2-acetamidoacrylate 1, under iron(III) chloride catalysis.
- Perez,Pleixats
-
p. 8355 - 8362
(2007/10/02)
-