- Synthesis and evaluation of chloromethyl sulfoxides as a new class of selective irreversible cysteine protease inhibitors
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The synthesis and biological evaluation of a new class of selective irreversible cysteine protease inhibitors is described. A set of amino acid based chloromethyl sulfoxides was prepared and they were found to inhibit irreversibly the cysteine protease papain. They were selective for cysteine proteases since no inhibition was found for the serine protease chymotrypsin.
- Brouwer, Arwin J.,Bunschoten, Anton,Liskamp, Rob M.J.
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Read Online
- Case studies in process screening and optimization utilizing a new automated reactor - Analysis system
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The application of a new automated workstation for conducting solution-phase reactions in parallel during chemical process development is described. The fully automated reactor - analysis system is capable of reagent/reactant addition, temperature and agitation control, and sample extraction/quench/injection for online HPLC analysis. Both precision and accuracy of the fluidic delivery and sampling systems were measured through the use of standard ultraviolet chromophore solutions in conjunction with HPLC analysis. Agitation efficiency was evaluated using a phase-transfer catalysis reaction known to be rate-dependent on stirring frequency. Chemistry cases examined included several single and multistep reactions studied to identify the best reagent/solvent combinations (screening) and optimal levels of continuous variables such as temperature, concentration, and stoichiometry (optimization). A multistep route to a chiral substituted imidazolidin-2-one was developed from initial route scouting through reaction condition screening, optimization, and scale-up. Reactions performed included alkylation, reduction, oxidation, reductive amination, displacement, and cyclization.
- Gooding, Owen W.,Lindberg, Thomas,Miller, Wendy,Munyak, Edward,Vo, Lanchi
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Read Online
- Clickable coumarins as fluorescent labels for amino acids
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Seven trifunctional conjugates of Fmoc-protected amino acids with alkynyloxy-substituted coumarins have been prepared and spectroscopically characterized. The coumarin core was either coupled to the α or side chain amino group. This design allows for the
- Mertens, Matthias D.,Gütschow, Michael
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Read Online
- USP30 INHIBITORS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of USP30, and the treatment of USP30-mediated disorders.
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Paragraph 00573-00574
(2021/03/19)
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- Development of Chiral Organosuperbase Catalysts Consisting of Two Different Organobase Functionalities
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In the field of chiral Br?nsted base catalysis, a new generation of chiral catalysts has been highly anticipated to overcome the intrinsic limitation of pronucleophiles that are applicable to the enantioselective reactions. Herein, we reveal conceptually new chiral Br?nsted base catalysts consisting of two different organobase functionalities, one of which functions as an organosuperbase and the other as the substrate recognition site. Their prominent activity, which stems from the distinctive cooperative function by the two organobases in a single catalyst molecule, was demonstrated in the unprecedented enantioselective direct Mannich-type reaction of α-phenylthioacetate as a less acidic pronucleophile. The present achievement would provide a new guiding principle for the design and development of chiral Br?nsted base catalysts and significantly broaden the utility of Br?nsted base catalysis in asymmetric organic synthesis.
- Kondoh, Azusa,Oishi, Masafumi,Terada, Masahiro,Tezuka, Hikaru
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supporting information
p. 7472 - 7477
(2020/03/19)
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- Asymmetric kinetic resolution of sulfides for the construction of unsymmetric sulfides and chiral 3,3-disubstituted oxindoles
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A range of 3,3-disubstituted oxindoles accessed using para-quinone methides derived from isatins with thiols were used for the formation of unsymmetrical disulfides, and 3,3-disubstituted oxindoles with a chiral quaternary carbon center and unsymmetric di
- Wang, Kaiye,Xiang, Yanan,Shi, Zhujun,Wang, Hongyu,Li, Na,Tang, Bo
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p. 6351 - 6354
(2019/07/10)
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- Synthesis and evaluation of chirally defined side chain variants of 7-chloro-4-aminoquinoline to overcome drug resistance in malaria chemotherapy
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A novel 4-aminoquinoline derivative [(S)-7-chloro-N-(4-methyl-1-(4-methyl-piperazin-1-yl)pentan-2-yl)-quinolin-4-amine triphosphate] exhibiting curative activity against chloroquine-resistant malaria parasites has been identified for preclinical development as a blood schizonticidal agent. The lead molecule selected after detailed structure-activity relationship (SAR) studies has good solid-state properties and promising activity against in vitro and in vivo experimental malaria models. The in vitro absorption, distribution, metabolism, and excretion (ADME) parameters indicate a favorable drug-like profile.
- Dola, Vasantha Rao,Soni, Awakash,Agarwal, Pooja,Ahmad, Hafsa,Raju, Kanumuri Siva Rama,Rashid, Mamunur,Wahajuddin, Muhammad,Srivastava, Kumkum,Haq,Dwivedi,Puri,Katti
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- Synthesis and antimalarial activity of new 4-aminoquinolines active against drug resistant strains
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In the present study we have synthesized a new class of 4-aminoquinoline derivatives via replacement of the diethylamine functionality of chloroquine (CQ) with acyclic and/or cyclic amine groups containing basic tertiary terminal nitrogen and bioevaluated them for antimalarial activity against Plasmodium falciparum in vitro (CQ-sensitive strain-3D7 & CQ-resistant strain-K1) and Plasmodium yoelii in vivo (N-67 strain). Among the series, thirteen compounds showed superior antimalarial activity against K1 strain as compared to CQ. In addition, all these analogs showed 100% suppression of parasitaemia on day 4 in the in vivo mouse model against N-67 strain when administered orally. Further, biophysical studies suggest that these compounds act on the heme polymerization target.
- Kondaparla, Srinivasarao,Soni, Awakash,Manhas, Ashan,Srivastava, Kumkum,Puri, Sunil K.,Katti
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p. 105676 - 105689
(2016/11/18)
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- N a aminopeptidase inhibitor and its preparation method and application
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The invention discloses an aminopeptidase N inhibitor which has a chemical name of 2-((S)-3-(3-((S)-2-amino-3-phenylpropyl)urea)-2,6-dioxopiperidine-1-yl)-N-hydroxyacetamide hydrochloride and is a compound with a structural formula (I) described in the sp
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Paragraph 0016-0018; 0024; 0031; 0032
(2017/01/23)
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- HETEROARYL SUBSTITUTED AMINOPYRIDINE COMPOUNDS
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Disclosed are compounds of Formula (I) or salts thereof, wherein HET is a heteroaryl selected from pyrrolo[2,3 b]pyridinyl, pyrrolo[2,3 d]pyrimidinyl, pyrazolo[3,4 b]pyridinyl, pyrazolo[3,4 d]pyrimidinyl, imidazolo[4,5 b]pyridinyl, and imidazolo[4,5 d]pyrimidinyl, wherein said heteroaryl is attached to the pyridinyl group in the compound of Formula (I) by a nitrogen ring atom in said heteroaryl and wherein said heteroaryl is substituted with zero to 2 Rb; A is pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxadiazolyl or dihydroisoxazolyl, each substituted with zero or 1 Ra; and R3, Ra, and Rb are define herein. Also disclosed are methods of using such compounds as modulators of IRAK4, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing inflammatory and autoimmune diseases, or in the treatment of cancer.
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Page/Page column 133-134
(2017/01/09)
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- METHODS FOR INHIBITING DRUG DEGRADATION
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Methods of inhibiting cytochrome P450 enzymes are provided that can be used for improving the treatment of diseases by preventing degradation of drugs or other molecules by cytochrome P450. Pharmaceutical compositions are provided that can act as boosters
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Paragraph 0244; 0245
(2015/11/02)
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- A multifaceted secondary structure mimic based on piperidine-piperidinones
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Minimalist secondary structure mimics are typically made to resemble one interface in a protein-protein interaction (PPI), and thus perturb it. We recently proposed suitable chemotypes can be matched with interface regions directly, without regard for secondary structures. Here we describe a modular synthesis of a new chemotype 1, simulation of its solution-state conformational ensemble, and correlation of that with ideal secondary structures and real interface regions in PPIs. Scaffold 1 presents amino acid side-chains that are quite separated from each other, in orientations that closely resemble ideal sheet or helical structures, similar non-ideal structures at PPI interfaces, and regions of other PPI interfaces where the mimic conformation does not resemble any secondary structure. 68 different PPIs where conformations of 1 matched well were identified. A new method is also presented to determine the relevance of a minimalist mimic crystal structure to its solution conformations. Thus dld-1-faf crystallized in a conformation that is estimated to be 0.91 kcal-mol-1 above the minimum energy solution state. Do we know, when designing a new peptidomimetic scaffold like the one shown, how it can resemble secondary structures? Design and modular synthesis of this elongated mimic is reported, and the structure is related to ideal and real structures at PPI interfaces.
- Xin, Dongyue,Perez, Lisa M.,Ioerger, Thomas R.,Burgess, Kevin
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p. 3594 - 3598
(2014/04/17)
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- Structure-activity relationships of diamine inhibitors of cytochrome P450 (CYP) 3A as novel pharmacoenhancers, part I: Core region
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Ritonavir (RTV), an HIV-1 protease inhibitor (PI), is also a potent mechanism-based inhibitor of human cytochrome P450 3A (CYP3A) and has been widely prescribed as a pharmacoenhancer. As a boosting agent for marketed PIs, it reduces pill burden, and improves compliance. Removal of the hydroxyl group from RTV reduces, but does not eliminate HIV PI activity and does not affect CYP3A inhibition. Herein we report the discovery of a novel series of CYP3A inhibitors that are devoid of antiviral activity. The synthesis and evaluation of analogs with extensive modifications of the 1,4-diamine core along with the structure activity relationships with respect to anti-HIV activity, CYP3A inhibitory activity, selectivity against other CYP enzymes and the human pregnane X receptor (PXR) will be discussed.
- Liu, Hongtao,Xu, Lianhong,Hui, Hon,Vivian, Randy,Callebaut, Christian,Murray, Bernard P.,Hong, Allen,Lee, Melody S.,Tsai, Luong K.,Chau, Jennifer K.,Stray, Kirsten M.,Cannizzaro, Carina,Choi, You-Chul,Rhodes, Gerry R.,Desai, Manoj C.
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p. 989 - 994
(2014/02/14)
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- Helix-forming propensity of aliphatic urea oligomers incorporating noncanonical residue substitution patterns
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Aliphatic N,N′-linked oligoureas are peptidomimetic foldamers that adopt a well-defined helical secondary structure stabilized by a collection of remote three-center H-bonds closing 12- and 14-membered pseudorings. Delineating the rules that govern helix formation depending on the nature of constituent units is of practical utility if one aims to utilize this helical fold to place side chains in a given arrangement and elaborate functional helices. In this work, we tested whether the helix geometry is compatible with alternative substitution patterns. The central -NH-CH(R)-CH2-NH-CO- residue in a model oligourea pentamer sequence was replaced by guest units bearing various substitution patterns [e.g., -NH-CH2-CH2-NH-CO-, -NH-CH2-CH(R)-NH-CO-, and -NH-CH(R1)-CH(R 2)-NH-CO-], levels of preorganization (cyclic vs acyclic residues), and stereochemistries, and the helix formation was systematically assessed. The extent of helix perturbation or stabilization was primarily monitored in solution by Fourier transform IR, NMR, and electronic circular dichroism spectroscopies. Our results indicate that although three new substitution patterns were accommodated in the 2.5-helix, the helical urea backbone in short oligomers is particularly sensitive to variations in the residue substitution pattern (position and stereochemistry). For example, the trans-1,2- diaminocyclohexane unit was experimentally found to break the helix nucleation, but the corresponding cis unit did not. Theoretical calculations helped to rationalize these results. The conformational preferences in this series of oligoureas were also studied at high resolution by X-ray structure analyses of a representative set of modified oligomers.
- Pendem, Nagendar,Douat, Celine,Claudon, Paul,Laguerre, Michel,Castano, Sabine,Desbat, Bernard,Cavagnat, Dominique,Ennifar, Eric,Kauffmann, Brice,Guichard, Gilles
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supporting information
p. 4884 - 4892
(2013/05/09)
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- Catalytic asymmetric [4+2] annulation initiated by an aza-rauhut-currier reaction: Facile entry to highly functionalized tetrahydropyridines
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Under control: The first example of chiral amino phosphine catalysts for the title reaction between vinyl ketones and N-sulfonyl-1-aza-1,3-dienes has been developed. Under ambient conditions, this protocol provides straightforward access to densely functionalized, enantioenriched tetrahydropyridines with high levels of sterecontrol in good to excellent yields. Copyright
- Shi, Zugui,Yu, Peiyuan,Loh, Teck-Peng,Zhong, Guofu
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p. 7825 - 7829
(2012/09/08)
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- 4-ARYL-BUTANE-1,3-DIAMIDES
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The invention relates to compound of the formula (I): in which the substituents are as defined in the specification; in free form or in salt form; to its preparation, to its use as medicament and to medicaments comprising it.
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Page/Page column 73
(2011/07/07)
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- Bimetallic system for the synthesis of diorganyl selenides and sulfides, chiral β-seleno amines, and seleno- and thioesters
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The bimetallic reagent Sn(II)/Cu(II) in [bmim]BF4 was efficiently used for the cleavage of diaryl diselenides and disulfides and reacts with a variety of organic substrates, such as organic halides, acid chlorides, and β-amino mesylates affording the diorganyl selenides and sulfides within very short reaction times, under mild conditions and with excellent yields, using BMIM-BF4 as a reusable solvent.
- Gul, Kashif,Narayanaperumal, Senthil,Dornelles, Luciano,Rodrigues, Oscar E.D.,Braga, Antonio Luiz
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supporting information; experimental part
p. 3592 - 3596
(2011/07/31)
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- Discovery and development of an efficient, scalable, and robust route to the novel CENP-E inhibitor GSK923295A
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The discovery and development of an efficient manufacturing route to the CENP-E inhibitor 3-chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)- 1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl} -4-[(1-methylethyl)oxy]benzamide (GSK923295A) is described. The existing route to GSK923295A was expensive, nonrobust, used nonideal reagents, and consistently struggled to deliver the API needed for clinical studies. The new synthesis commences from the readily available l-phenylalaninol, which is smoothly converted through to GSK923295A using key Friedel-Crafts acylation as well as selective acylation chemistries. Downstream chemistry to GSK923295A is both high yielding and robust, and the resulting process has been demonstrated first on the kilo scale and subsequently in the pilot plant where 55 kg was successfully prepared. The resulting process is simple, uses cheaper raw materials, is greener in that it avoids using aluminum, tin, and bromination chemistries, and obviates the need for chromatographic purification. Also discussed are the route derived impurities, how they were unambiguously prepared to confirm structure and processing amendments to control their formation, and enhancements to the new process to facilitate future processing.
- Bellingham, Richard,Buswell, A. Mark,Choudary, Bernie M.,Gordon, Andrew H.,Moore, Steve O.,Peterson, Matthew,Sasse, Mike,Shamji, Amin,Urquhart, Michael W. J.
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p. 1254 - 1263
(2011/04/24)
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- 4-ARYL-BUTANE-1,3-DIAMIDES
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The invention relates to compound of the formula (1) in which the substituents are as defined in the specification; m free form or in salt form; to its preparation, to its use as medicament and to medicaments comprising it.
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Page/Page column 39; 40
(2010/08/09)
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- Asymmetrie [3+2] cycloadditions of allenoates and dual activated olefins catalyzed by simple bifunctional N-acyl aminophosphines
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(Figure Presented) Bifunctional catalyst: Simple bifunctional N-Acyl aminophosphines such as 1 were developed to catalyze the first asymmetric [3+2] cycloaddition between allenoates and dual activated olefins. The cycloaddi- tion reactions afford multifun
- Xiao, Hua,Chai, Zhuo,Zheng, Chang-Wu,Yang, Ying-Quan,Liu, Wen,Zhang, Jun-Kang,Zhao, Gang
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supporting information; experimental part
p. 4467 - 4470
(2010/07/16)
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- Entropy-controlled catalytic asymmetric 1,4-type Friedel-crafts reaction of phenols using conformationally flexible guanidine/bisthiourea organocatalyst
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Soft and weak cooperation: Conformationally flexible organic compounds were found to promote the title transformation. These "soft" organocatalysts, which are able to control processes through the differential activation entropies (ΔΔS*S-R) of
- Sohtome, Yoshihiro,Shin, Bongki,Horitsugi, Natsuko,Takagi, Rika,Noguchi, Keiichi,Nagasawa, Kazuo
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supporting information; experimental part
p. 7299 - 7303
(2010/11/04)
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- Synthesis and evaluation of inhibitors of cytochrome P450 3A (CYP3A) for pharmacokinetic enhancement of drugs
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The HIV protease inhibitor ritonavir (RTV) is also a potent inhibitor of the metabolizing enzyme cytochrome P450 3A (CYP3A) and is clinically useful in HIV therapy in its ability to enhance human plasma levels of other HIV protease inhibitors (PIs). A nov
- Flentge, Charles A.,Randolph, John T.,Huang, Peggy P.,Klein, Larry L.,Marsh, Kennan C.,Harlan, John E.,Kempf, Dale J.
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supporting information; experimental part
p. 5444 - 5448
(2010/05/02)
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- HIV PROTEASE INHIBITOR AND CYTOCHROME P450 INHIBITOR COMBINATIONS
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Compositions and methods of treating viral infections are provided. More particularly, compositions including a combination of protease inhibitors and cytochrome p450 enzyme inhibitors are provided. Methods of using the compositions for treatment of disea
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Page/Page column 42
(2009/10/18)
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- COMPOSITIONS AND METHODS FOR INHIBITING CYTOCHROME P450
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Methods of inhibiting cytochrome P450 enzymes are provided that can be used for improving the treatment of diseases by preventing degradation of drugs or other molecules by cytochrome P450. Pharmaceutical compositions are provided that can act as boosters
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Page/Page column 45
(2008/06/13)
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- Amino-substituted heterocycles, compositions thereof, and methods of treatment therewith
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Provided herein are Heterocyclic Compounds having the following structure: wherein R1, R2, X, Y and Z are as defined herein, compositions comprising an effective amount of a Heterocyclic Compound and methods for treating or preventing cancer, inflammatory conditions, immunological conditions, metabolic conditions and conditions treatable or preventable by inhibition of a kinase pathway comprising administering an effective amount of a Heterocyclic Compound to a patient in need thereof.
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Page/Page column 54
(2008/12/07)
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- (INDAZOL-5-YL)-PYRAZINES AND (1,3-DIHYDRO-INDOL-2-ONE)-PYRAZINES FOR TREATING RHO KINASE-MEDIATED DISEASES AND CONDITIONS
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Methods for using (indazol-5-yl)-pyrazines and (1,3-dihydro-indol-2-one)-pyrazines are disclosed herein to treat rho kinase-mediated diseases or rho kinase-mediated conditions, including controlling intraocular pressure and treating glaucoma, are disclosed. Ophthalmic pharmaceutical compositions useful in the treatment of eye diseases such as glaucoma, and additionally useful for controlling intraocular pressure, the compositions comprising an effective amount of (indazol-5-yl)-pyrazines and (1,3-dihydro-indol-2-one)-pyrazines, are disclosed herein.
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Page/Page column 7
(2010/11/27)
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- Novel compounds that are useful for improving pharmacokinetics
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Novel compounds of formula 1 or a pharmaceutically acceptable salt thereof inhibit cytochrome P450 monooxygenase.
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Page/Page column 25
(2008/06/13)
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- Convergent synthesis and diversity of amino acid based dendrimers
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The synthesis of amino acid based dendrimers 25 (fifth generation, 32 endgroups), 30 (fourth generation, 81 endgroups), chiral dendrimer 23 (third generation, 8 endgroups) as well as core-modified dendrimers 34 and 38 by the convergent method is described. The amino acid building blocks are derived from hydroxybenzoic acid derivatives and amino alcohol derivatives, and access to a considerable molecular diversity of these novel dendrimers can be achieved, The synthesis can be carried out on a relatively large scale, and this easy access of the dendrimers may lead to many potential applications.
- Brouwer, Arwin J.,Mulders, Suzanne J. E.,Liskamp, Rob M. J.
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p. 1903 - 1915
(2007/10/03)
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- Synthesis of homochiral N-Boc-β-aminoaldehydes from N-Boc-β-aminonitriles
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Enantiopure N-Boc-β-aminoaldehydes are efficiently prepared in good yields from N-Boc-β-aminonitriles by reduction of the nitrile function with diisobutylaluminium hydride (DIBAL-H) - Keywords: β-aminoaldehyde; β-aminonitrile; α-aminoacid; homochiral; enantiomeric excess; reduction; DIBAL-H
- Toujas, Jean-Louis,Jost, Eric,Vaultier, Michel
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p. 713 - 718
(2007/10/03)
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- Molecular diversity of novel amino acid based dendrimers
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We have expanded the recently introduced methodology for the preparation of a novel amino acid based dendrimer in order to be able to synthesize a diversity of dendrimers. For this purpose different hydroxybenzoic acids and amino alcohols were used to prepare the required monomers, necessary for construction of the respective dendrimers.
- Mulders, Suzanne J. E.,Brouwer, Arwin J.,Liskamp, Rob M. J.
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p. 3085 - 3088
(2007/10/03)
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- Synthesis of Peptidosulfinamides and Peptidosulfonamides: Peptidomimetics Containing the Sulfinamide or Sulfonamide Transition-State Isostere
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Synthetic routes are described toward the preparation of α- as well as β-substituted aminoethanesulfinyl chlorides, starting from either an aldehyde or from an amino acid derivative.The sulfinyl chlorides are used as building blocks for the preparation of homochiral α- or β-substituted sulfinamide and sulfonamide transition-state isosteres.The methodology has been applied to the synthesis of peptidosulfonamide peptidomimetics such as a hapten needed for the generation of antibodies and potential HIV protease inhibitors.In addition, the β-substituted aminoethanesulfinyl chlorides were used as building blocks for the preparation of a tetrapeptidosulfonamide, which can be considered as a biopolymer mimetic, employing a repetition of a cycle of three reactions: coupling of the sulfinyl chloride to the N-terminus of the growing peptidosulfonamide, oxidation to the sulfonamide, and deprotection of the N-terminus.
- Moree, Wilna J.,Marel, Gijs A. van der,Liskamp, Rob J.
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p. 5157 - 5169
(2007/10/02)
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- Conversion of chiral amino acids to enantiomerically pure α-methylamines
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Enantiomerically enriched α-methylamines are obtained in high yield by Raney nickel reduction of N-Boc-protected, amino acid-derived thioethers.
- Donner
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p. 1223 - 1226
(2007/10/02)
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- Inhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 8. Incorporation of amide or amine functionalities into a series of disubstituted ureas and carbamates. Effects of ACAT inhibition in vitro and efficacy in vivo
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A series of disubstituted ureas containing amide or amine groups was prepared and evaluated for their ability to inhibit acyl-CoA:cholesterol O- acyl transferase in vitro and to lower plasma total cholesterol in a variety of cholesterol-fed rat models in vivo. The presence of polar or ionizable functionalities within this class of compounds may impart greater aqueous solubility to those compounds and thus allow improved transport to the enzyme location within the intestinal enterocyte. Compounds from this class exhibit good cholesterol lowering in a chronic cholesterol-fed rat model of hypercholesterolemia even when dosed in an aqueous vehicle. In general, the amine-containing compounds were more potent and efficacious than the amides in the acute rat model of hypercholesterolemia. Further structure-activity relationship studies showed that the preferred position of the amide/amine group was β to the urea moiety and not α, and that in this series, the presence of a secondary amine (or amide) proton is required for good in vitro potency. One of these compounds, 9n(-), lowered plasma total cholesterol (- 47%) and elevated high-density lipoprotein cholesterol (+256%) when dosed in an aqueous vehicle to rats with preestablished hypercholesterolemia.
- O'Brien,Sliskovic,Blankley,Roth,Wilson,Hamelehle,Krause,Stanfield
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p. 1810 - 1822
(2007/10/02)
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- Benzoxazolamines and Benzothiazolamines: Potent, Enantioselective Inhibitors of Leukotriene Biosynthesis with a Novel Mechanism of Action
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A series of benzoxazolamine and benzothiazolamine analogs that inhibit leukotriene (LT) biosynthesis are described.The initial lead, (S)-N-(benzothiazol-2-yl)phenylalanine ethyl ester (5a), was discovered in a screening program for inhibition of Ca-ionophore-A23187-induced LTB4 release in human polymorphonuclear leukocytes (IC50 0.23 μM).Through structural modification, it was determined that hydrophobic substituents in the 5-position and replacement of the phenyl ring of phenylalanine with a cyclohexyl group greatly enhance potency.Several ester bioisosteres that retain potency and enantiomeric selectivity are described.Lead optimization culminated in (S)-N--5-methyl-2-benzoxazolamine (43b), IC50 0.001 μM.The compounds described are not inhibitors of 5-lipoxygenase but, rather, act at the level of arachidonic acid release.
- Lazer, Edward S.,Miao, Clara K.,Wong, Hin-Chor,Sorcek, Ronald,Spero, Denice M.,et al.
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p. 913 - 923
(2007/10/02)
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- Synthesis of peptides containing the β-substituted aminoethane sulfinamide or sulfonamide transition-state isostere derived from amino acids
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α-amino acids can be converted to homochiral β-substituted aminoethane sulfinamide or sulfonamide transition-state isosteres, which can be incorporated into peptides. These transition-state analogues e.g. the sulfonamide isostere of Phe-Phe will be used for the generation of catalytic antibodies as well as for the development of protease inhibitors.
- Moree, Wilna J.,Van Der Marel, Gijs A.,Liskamp Rob
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p. 6389 - 6392
(2007/10/02)
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- Modified Amino Acids and Peptides. Part 2. A Convenient Conversion of Amino and Peptide Alcohols into Amines.
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A convenient general method for the conversion of N-protected amino and peptide alcohols into amines is described.The hydroxyl group of the alcohols was replaced by an azido group and a substituted amino group after activation through mesylation.Hydrogenation of the N-protected amino azides afforded optically active monoprotected diamines or free 1,2-diamines depending on the N-protecting group.Selective reduction of the azido group in the presence of a benzyloxycarbonyl group was performed in high yield using sodium borohydride in the presence of 10percent palladium on charcoal.
- Kokotos, George,Constantinou-Kokotou, Violetta
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p. 3117 - 3132
(2007/10/02)
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- Syntheses and Properties of Optically Active 2-Substituted Taurines
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The synthesis of nine 2-substituted taurines (5a-i), including the marine natural product D-cysteinolic acid (5f), are described.These involve the successive conversion of N-t-butoxycarbonyl(Boc)-protected amino acid esters (1) into the N-Boc-2-aminoethanols (2), their O-mesylated derivatives (3), the deprotected 2-aminoethyl methanesulphonates (4), followed by the replacement of the mesyloxy group by a sulpho group to give the optically active taurines (5a-e,g-i).Hydrogenolysis of 2-benzyloxymethyltaurine (5e) gives D-cysteinolic acid (5f).The structure of another of the products, (5b), is also confirmed by an alternative synthesis from N-Boc-valine methyl ester (1b) via twoβ-bromoethylamine derivatives, (6b) and (7b).
- Higashiura, Kunihiko,Morino, Hiroe,Matsuura, Hirohide,Toyomaki, Yoshio,Ienaga, Kazuharu
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p. 1479 - 1481
(2007/10/02)
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- New Approaches to the Synthesis of trans-Alkene Isosteres of Dipeptides
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Two new syntheses of protected dipeptide analogues bearing a trans carbon-carbon double bond in place of the amide linkage are reported.One route is a linear synthesis employing the rearrangement of an allylic selenide to a protected allylic amine.The second route is convergent and uses the Julia olefin synthesis in a key step.The latter route is fully stereocontrolled and has been used to prepare protected trans-alkene isosteres of the dipeptides TyrAla, PhePhe, LeuPhe, and LeuLeu.
- Spaltenstein, Andreas,Carpino, Philip A.,Miyake, Fumio,Hopkins, Paul B.
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p. 3759 - 3766
(2007/10/02)
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- A STEREOCONTROLLED SYNTHESIS OF TRANS-ALKENE ISOSTERES OF DIPEPTIDES
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A general synthetic route to trans-alkene isosteres of protected dipeptides is reported.This sequence permits the fully stereocontrolled preparation of these isosteres in optically active form and in quantities sufficient for further biological study.Prep
- Spaltenstein, Andreas,Carpino, Philip A.,Miyake, Fumio,Hopkins, Paul B.
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p. 2095 - 2098
(2007/10/02)
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