- Efficient Multikilogram Synthesis of a VLA-4 Antagonist via a Povarov Reaction
-
Herein we describe the practical synthesis of a novel VLA-4 antagonist 1 as a potential treatment for multiple sclerosis. The key step is based on the Povarov reaction of an imine with an alkene to access a tetrahydroquinoline intermediate, leading to the corresponding quinoline core after an oxidative aromatization step. The development of the synthesis of 1 led to decreased complexity and the elimination of chromatographic purifications. These improvements were demonstrated at scale by the production of 32 kg of 1 in high yield with excellent purity.
- Cerfontaine, Patrick,Driessens, Frank,Deltent, Marie-France,Petit, Sylvain
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p. 807 - 816
(2019/12/24)
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- Rhodium-Catalyzed Enantioselective Synthesis of Oxazinones via an Asymmetric Ring Opening-Lactonization Cascade of Oxabicyclic Alkenes
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The rhodium-catalyzed asymmetric ring opening reaction of oxabicyclic alkenes is shown to be an efficient method for synthesizing chiral heterocycles. We demonstrate that the pairwise combination of chiral catalyst with chiral amino-acid-derived pronucleophiles results in a stereodivergent synthesis of diastereomeric hydroxyesters. A favorable conformational preference induces the subsequent lactonization of one diastereomer leading to the highly enantioselective synthesis of oxazinones.
- Yen, Andy,Pham, Anh Hoang,Larin, Egor M.,Lautens, Mark
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supporting information
p. 7549 - 7553
(2019/10/02)
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- Tuning the reaction pathways of phenanthroline-Schiff bases: Routes to novel phenanthroline ligands
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Pyrido-phenanthrolin-7-one compounds are structural analogues of the cytotoxic alkaloid, ascididemin, and would be expected to have interesting biological activities. Synthetic strategies are reported for a novel simple route to form this class of ligand. 1,10-Phenanthrolin-5,6-dione reacts with l-phenylalanine alkyl esters and their para-substituted analogues to form both a phenanthroline-oxazine and a pyrido-phenanthrolin-7-one product. The nature of the major product is dependent on the electronic properties of the para substituent. Successful metal coordination to the pyrido-phenanthrolin-7-one ligand is also presented.
- Ahmed, Muhib,Rooney, Denise,McCann, Malachy,Casey, Jamie,O'Shea, Katie,Twamley, Brendan
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p. 15283 - 15289
(2019/10/22)
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- Substituted Dihydroisoquinolinones by Iodide-Promoted Cyclocarbonylation of Aromatic α-Amino Acids
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Imidazolidinone derivatives of a range of aromatic α-amino acids, on treatment with phosgene and potassium iodide, undergo a mild Bischler-Napieralski-style cyclocarbonylation reaction that generates a tricyclic lactam by insertion of a C=O group between amino acid nitrogen and the ortho position of the aryl substituent. Regio- and diastereoselective functionalization of the lactam generates a library of substituted dihydroisoquinolinones and their congeners in enantioenriched form.
- Amer, Mostafa M.,Carrasco, Ana C.,Leonard, Daniel J.,Ward, John W.,Clayden, Jonathan
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supporting information
p. 7977 - 7981
(2019/01/04)
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- Chiral GAP catalysts of phosphonylated imidazolidinones and their applications in asymmetric Diels-Alder and Friedel-Crafts reactions
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The design and synthesis of recyclable imidazolidinone catalysts using GAP chemistry/technique was described. Their applications in asymmetric Diels-Alder and Friedel-Crafts reactions with α,β-unsaturated aldehydes resulted in excellent yields and higher enantioselectivities than previous processes. As recyclable small molecular catalysts, phosphonylated imidazolidinones can be recovered and reused for up to three runs without costing significant decrease in catalytic activity.
- Qiao, Shuo,Mo, Junming,Wilcox, Cody B.,Jiang, Bo,Li, Guigen
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p. 1718 - 1724
(2017/02/23)
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- An Optically Active Polymer for Broad-Spectrum Enantiomeric Recognition of Chiral Acids
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Recognition of enantiomers of chiral acids by anion–π or lone pair–π interactions has not yet been investigated but is a significant and attractive challenge. This study reports an optically active polymer-based supramolecular system with capabilities of discriminating enantiomers of various chiral acids. The polymer featuring alternate π-acidic naphthalenediimides (NDIs) and methyl l-phenylalaninates in the backbone exhibits an unprecedented slow self-assembly process that is susceptible to perturbation by various chiral acids. Thus, the combination of anion–π or lone pair–π interactions and sensitivity of the polymeric self-assembly process to external chiral species endows the system with recognition capabilities. This is the first time that anion–π or lone pair–π interactions have been applied in the recognition of enantiomers of various chiral acids with a single system. The results shed light on new strategies for material design by integrating π-acidic aromatic systems and chiral building blocks to afford relevant advanced functions.
- Yan, Jijun,Kang, Chuanqing,Bian, Zheng,Ma, Xiaoye,Jin, Rizhe,Du, Zhijun,Gao, Lianxun
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p. 5824 - 5829
(2017/04/28)
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- Supramolecular self-assembly of chiral polyimides driven by repeat units and end groups
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Pyromellitic diimides (PMDIs) are effective building blocks for the construction of supramolecular systems but are infrequently used in comparison with other electron-deficient aromatic systems. We report PMDI-based chiral polyimides that form polymeric supramolecular systems with unique self-assembly features that show time-dependent spectroscopic behaviour. Extensive investigations revealed the driving forces for the self-assembly of the polyimides. One is the complementary aromatic π-π stacking between electron-accepting PMDI and electron-donating phenyl ring in the polymer backbones, and another is the hydrogen bonding interactions of the end groups. The self-assembly is readily disrupted by guest molecules with strong associations with the PMDI and the end groups. The introduction of flexible arylether diimides into the PMDI-based copolymer backbones and the sequence of PMDIs and arylether diimides in the copolymer backbones significantly influence the self-assembly of the polyimides. The results elucidate the mechanisms of polymeric self-assembly of chiral polyimides, providing important information for the development of materials based on polymeric supramolecular systems with properties and functions regulated by composition, sequence and end groups.
- Yan, Jijun,Kang, Chuanqing,Bian, Zheng,Jin, Rizhe,Ma, Xiaoye,Gao, Lianxun
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p. 14723 - 14729
(2017/11/28)
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- Specific molecular marked heavy-metal chelating agent, corresponding rapid chromatographic detection card and application
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The invention relates to a specific molecular marked heavy-metal chelating agent, corresponding detection technologies and application. The heavy-metal chelating agent disclosed by the invention is metal chelating molecules marked by specific marking molecules; after being combined with heavy metal, one ends of the molecules can be identified and captured by an antibody; the marking molecules at the other ends are combined with a corresponding ligand or antibody; therefore, sandwich detection is realized; and the detection technologies comprise an enzyme-linked immune technology and a rapid paper chromatographic technology. By means of the specific molecular marked heavy-metal chelating agent, the corresponding detection technologies and application disclosed by the invention, rapid sandwich detection on metal ion can be realized for the first time; requirements of conventional heavy-metal detection on an expensive instrument can be avoided; and thus, disadvantages of the sensitivity and the specificity of a competition-method heavy-metal rapid detection card can be made up.
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-
Paragraph 0030; 0032; 0039; 0041
(2017/08/28)
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- Distal Stereocontrol Using Guanidinylated Peptides as Multifunctional Ligands: Desymmetrization of Diarylmethanes via Ullman Cross-Coupling
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We report the development of a new class of guanidine-containing peptides as multifunctional ligands for transition-metal catalysis and its application in the remote desymmetrization of diarylmethanes via copper-catalyzed Ullman cross-coupling. Through design of these peptides, high levels of enantioinduction and good isolated yields were achieved in the long-range asymmetric cross-coupling (up to 93:7 er and 76% yield) between aryl bromides and malonates. Our mechanistic studies suggest that distal stereocontrol is achieved through a Cs-bridged interaction between the Lewis-basic C-terminal carboxylate of the peptides with the distal arene of the substrate.
- Kim, Byoungmoo,Chinn, Alex J.,Fandrick, Daniel R.,Senanayake, Chris H.,Singer, Robert A.,Miller, Scott J.
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supporting information
p. 7939 - 7945
(2016/07/07)
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- AMINO ACID DERIVATIVES AND ABSORBABLE POLYMERS THEREFROM
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The present invention relates to the discovery of new class of hydrolysable amino acid derivatives and absorbable polyester amides, polyamides, polyepoxides, polyureas and polyurethanes prepared therefrom. The resultant absorbable polymers are useful for drug delivery, tissue engineering, tissue adhesives, adhesion prevention, bone wax formulations, medical device coatings, stents, stent coatings, highly porous foams, reticulated foams, wound care, cardiovascular applications, orthopedic devices, surface modifying agents and other implantable medical devices. In addition, these absorbable polymers should have a controlled degradation profile.
- -
-
Paragraph 0243; 0244
(2016/09/26)
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- Asymmetric synthesis of 3,3,5,5-tetrasubstituted 1,2-dioxolanes: Total synthesis of epiplakinic acid F
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The first enantioselective total synthesis of epiplakinic acid F (1) was achieved through a pivotal step involving a radical-mediated asymmetric peroxidation of vinylcyclopropanes with molecular oxygen to construct highly substituted 1,2-dioxolanes. Subsequent conversions of the chiral 1,2-dioxolanes led to total synthesis of epiplakinic acid F (1) and the confirmation of its absolute configuration. The enantiomer of epiplakinic acid F methyl ester (2) was also prepared. This journal is the Partner Organisations 2014.
- Tian, Xiang-Yin,Han, Jian-Wei,Zhao, Qiong,Wong, Henry N. C.
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p. 3686 - 3700
(2014/06/09)
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- Asymmetric chemoenzymatic synthesis of N-acetyl-α-amino esters based on lipase-catalyzed kinetic resolutions through interesterification reactions
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Several phenylalanine analogs have been synthesized through a four-step route starting from easily available ethyl acetamidocyanoacetate. In a first reaction, and making use of phase transfer catalysts, this compound reacted with several alkyl halides, being benzyltributylammonium chloride identified as the best one for the production of a series of quaternary amino acids in moderate to excellent yields (52-95%). Then, the corresponding N-acetyl-phenylalanine methyl and allyl ester derivatives were obtained through acidic hydrolysis, esterification, and N-acetylation. Rhizomucor miehei lipase was found as a versatile enzyme for the resolution of these amino esters, finding the best results through interesterification reactions with butyl butyrate in acetonitrile. A great influence in the stereoselectivity was found depending on the chemical structure of the compound, achieving for the non- or para-substituted in the phenyl ring excellent stereoselectivities, being moderate for the meta-nitro derivative, while the ortho-nitro amino ester did not react.
- Da Silva, Marcos Reinaldo,De Mattos, Marcos Carlos,De Oliveira, Maria Da Concei??o Ferreira,De Lemos, Telma Leda Gomes,Ricardo, Nágila Maria Pontes Silva,De Gonzalo, Gonzalo,Lavandera, Iván,Gotor-Fernández, Vicente,Gotor, Vicente
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p. 2264 - 2271
(2014/03/21)
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- Modular construction of quaternary hemiaminal-based inhibitor candidates and their in cellulo assessment with HIV-1 protease
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Non-peptidomimetic drug-like protease inhibitors have potential for circumventing drug resistance. We developed a much-improved synthetic route to our previously reported inhibitor candidate displaying an unusual quaternized hemi-aminal. This functional group forms from a linear precursor upon passage into physiological media. Seven variants were prepared and tested in cellulo with our HIV-1 fusion-protein technology that result in an eGFP-based fluorescent readout. Three candidates showed inhibition potency above 20 μM and toxicity at higher concentrations, making them attractive targets for further refinement. Importantly, our class of original inhibitor candidates is not recognized by two major multidrug resistance pumps, quite in contrast to most clinically applied HIV-1 protease inhibitors.
- Gros, Guillaume,Martinez, Lorena,Gimenez, Anna Servat,Adler, Paula,Maurin, Philippe,Wolkowicz, Roland,Falson, Pierre,Hasserodt, Jens
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supporting information
p. 5407 - 5413
(2013/09/02)
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- Synthesis and biological evaluation of new active For-Met-Leu-Phe-OMe analogues containing para-substituted Phe residues
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In the present study, we report synthesis and biological evaluation of the N-Boc-protected tripeptides 4a-l and N-For protected tripeptides 5a-l as new For-Met-Leu-Phe-OMe (fMLF-OMe) analogues. All the new ligands are characterized by the C-terminal Phe residue variously substituted at position 4 of the aromatic ring. The agonism of 5a-l and the antagonism of 4a-l (chemotaxis, superoxide anion production, lysozyme release as well as receptor binding affinity) have been examined on human neutrophils. No synthesized compounds has higher activity than the standard fMLF-OMe tripeptide to stimulate chemotaxis, although compounds 5a and 5c with -CH3 and -C(CH3)3, respectively, in position 4 on the aromatic ring, are better than the standard tripeptide to stimulate the production of superoxide anion, in higher concentration. Compounds 4f and 4i, containing -F and -I in position 4, respectively, on the aromatic ring of phenylalanine, exhibit significant chemotactic antagonism. The influence of the different substitution at the position 4 on the aromatic ring of phenylalanine is discussed.
- Mollica, Adriano,Feliciani, Federica,Stefanucci, Azzurra,Costante, Roberto,Lucente, Gino,Pinnen, Francesco,Notaristefano, Daniela,Spisani, Susanna
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experimental part
p. 418 - 426
(2012/08/28)
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- Synthesis and bioactivity of novel 3-(1-hydroxyethylidene)-5-substituted- pyrrolidine-2,4-dione derivatives
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Ten novel 5-substituted derivatives of 3-(1-hydroxyethylidene)pyrrolidine- 2,4-dione were synthesized. The compounds were confirmed by IR, 1H NMR, MS and elemental analysis. The bioassay indicated that these compounds showed noticeable herbicid
- Han, Bao Feng,Shi, Qing Ming,Wang, Xian Feng,Liu, Jian Bo,Qiang, Sheng,Yang, Chun Long
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p. 1023 - 1026
(2012/10/08)
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- Synthesis and biological evaluation of Matijing-Su derivatives as potent anti-HBV agents
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A series of Matijing-Su (MTS, N-(N-benzoyl-l-phenylalanyl)-O-acetyl-l- phenylalanol) derivatives were synthesized and evaluated for their anti-hepatitis B virus (HBV) activity in 2.2.15 cells. The IC50 of compounds 14a (0.71 μM), 13c (2.85 μM), 13b (4.37 μM), etc. and the selective index of 13g (161.01), 13c (90.45), 13a (85.09) etc. of the inhibition on the replication of HBV DNA were better than those of the positive control lamivudine (IC50: 82.42 μM, SI: 41.59). Compounds 13o, 13p, and 16a also exhibited significant anti-HBV activity.
- Qiu, Jingying,Xu, Bixue,Huang, Zhengming,Pan, Weidong,Cao, Peixue,Liu, Changxiao,Hao, Xiaojiang,Song, Baoan,Liang, Guangyi
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p. 5352 - 5360
(2011/10/12)
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- Synthesis, in vitro progesterone receptors affinity of gadolinium containing mifepristone conjugates and estimation of binding sites in human breast cancer cells
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Novel gadolinium-based mifepristone conjugates were synthesised using various synthetic routes. Moderate antiprogestagenic activity of the new conjugates was observed in human breast cancer cells (T47-D cells) using AP (alkaline phosphatase) assay. The amount of incorporated Gd determined by inductively coupled plasma mass spectroscopy (ICPMS) indicates the number of binding sites per cell. These conjugates might be important compounds to develop receptor-targeted MRI contrast agents as well as other anti-breast cancer therapeutics.
- Saha, Pijus,H?dl, Claudia,Strauss, Wolfgang S.L.,Steiner, Rudolf,Goessler, Walter,Kunert, Olaf,Leitner, Alexander,Haslinger, Ernst,Schramm, H. Wolfgang
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experimental part
p. 1891 - 1898
(2010/05/17)
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- Synthesis and anti-hepatitis B virus activities of Matijing-Su derivatives
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A series of derivatives of Matijing-Su (MTS, N-(N-benzoyl-l-phenylalanyl)-O-acetyl-l-phenylalanol) was synthesized and evaluated for their anti-hepatitis B virus (HBV) activities in 2.2.15 cells. The IC50 of compounds 9c (1.40 μM), 9g (2.33 μM) and 9n (2.36 μM), etc. and the selective index of 9n (45.93) of the inhibition on the replication of HBV DNA were higher than those of the positive control lamivudine [41.59, (IC50: 82.42 μM)]. Compounds 11d, 12a and 12e also exhibited significant anti-HBV activities.
- Xu, Bixue,Huang, Zhengming,Liu, Changxiao,Cai, Zegui,Pan, Weidong,Cao, Peixue,Hao, Xiaojiang,Liang, Guangyi
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experimental part
p. 3118 - 3125
(2009/09/25)
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- Oleanolic acid and its derivatives: New inhibitor of protein tyrosine phosphatase 1B with cellular activities
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Protein tyrosine phosphatase 1B is a key factor in the negative regulation of insulin pathway and a promising target for treatment of diabetes and obesity. Herein, a series of competitive inhibitors were optimized from oleanolic acid, a natural triterpenoid identified against PTP1B by screening libraries of traditional Chinese medicinal herbs. Modifying at 3 and 28 positions, we obtained compound 13 with a Ki of 130 nM, which exhibited good selectivity between other phosphatases involved in insulin pathway except T-cell protein tyrosine phosphatase. Further evaluation in cell models illustrated that the derivatives enhanced insulin receptor phosphorylation in CHO/hIR cells and also stimulated glucose uptake in L6 myotubes with or addition of without insulin.
- Zhang, Yi-Nan,Zhang, Wei,Hong, Di,Shi, Lei,Shen, Qiang,Li, Jing-Ya,Li, Jia,Hu, Li-Hong
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p. 8697 - 8705
(2008/12/23)
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- Rational design and generation of a bimodal bifunctional ligand for antibody-targeted radiation cancer therapy
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An antibody-targeted radiation therapy (radioimmunotherapy, RIT) employs a bifunctional ligand that can effectively hold a cytotoxic metal with clinically acceptable complexation kinetics and stability while being attached to a tumor-specific antibody. Clinical exploration of the therapeutic potential of RIT has been challenged by the absence of adequate ligand, a critical component for enhancing the efficacy of the cancer therapy. To address this deficiency, the bifunctional ligand C-NETA in a unique structural class possessing both a macrocyclic cavity and a flexible acyclic moiety was designed. The practical, reproducible, and readily scalable synthetic route to C-NETA was developed, and its potential as the chelator of 212Bi, 213Bi, and 177Lu for RIT was evaluated in vitro and in vivo. C-NETA rapidly binds both Lu(III) and Bi(III), and the respective metal complexes remain extremely stable in serum for 14 days. 177Lu-C-NETA and 205/6Bi-C-NETA possess an excellent or acceptable in vivo biodistribution profile.
- Chong, Hyun-Soon,Ma, Xiang,Le, Thien,Kwamena, Baidoo,Milenic, Diane E.,Brady, Erik D.,Song, Hyun A.,Brechbiel, Martin W.
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p. 118 - 125
(2008/09/18)
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- Synthesis and evaluation of a novel samarium-153 bifunctional chelating agent for radioimmunotargeting applications
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A new bifunctional chelating agent (BCA), 3-(4-isothiocyanatobenzyl) triethylenetetraaminehexaacetic acid (9), has been synthesized in fast and easy conditions. An improved synthesis of its position isomer 1-(4- isothiocyanatobenzyl)triethylenetetraaminehexaacetic acid (19) is also described. Stability in serum media of the two corresponding aminobenzyl derivatives-samarium-153 complexes, respectively, 3-(4-aminobenzyl) triethylenetetraaminehexaacetic acid-samarium-153 and 1-(4-aminobenzyl) triethylenetetraaminehexaacetic acid-samarium-153, have been evaluated. The 3-(4-aminobenzyl)triethylenetetraaminehexaacetic acid complex revealed excellent stability in serum media, and therefore 3-(4-isothiocyanatobenzyl) triethylenetetraaminehexaacetic acid (9) appears useful for future in vivo radioimmunotherapy investigations. Copyright
- Morandeau, Laurence,Remaud-Le Saec, Patricia,Ouadi, Ali,Bultel-Riviere, Karine,Mougin-Degraef, Marie,De France-Robert, Agnes,Faivre-Chauvet, Alain,Gestin, Jean-Francois
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p. 109 - 123
(2007/10/03)
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- NOVEL PHENYLALANINE DERIVATIVE
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The present invention relates to the following phenylalanine derivatives or analogues thereof having an antagonistic activity to α4 integrin and therapeutic agents for various diseases concerning α4 integrin.
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- New phenylalanine derivatives
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Specified phenylalanine derivatives and analogues thereof have an antagonistic activity to α4 integrin. They are used as therapeutic agents for various diseases concerning α4 integrin.
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- GdIII complexes with fast water exchange and high thermodynamic stability: potential building blocks for high-relaxivity MRI contrast agents.
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On the basis of structural considerations in the inner sphere of nine-coordinate, monohydrated Gd(III) poly(aminocarboxylate) complexes, we succeeded in accelerating the water exchange by inducing steric compression around the water binding site. We modified the common DTPA(5-) ligand (DTPA=(diethylenetriamine-N,N,N',N",N"-pentaacetic acid) by replacing one (EPTPA(5-)) or two (DPTPA(5-)) ethylene bridges of the backbone by propylene bridges, or one coordinating acetate by a propionate arm (DTTA-prop(5-)). The ligand EPTPA(5-) was additionally functionalized with a nitrobenzyl linker group (EPTPA-bz-NO(2) (5-)) to allow for coupling of the chelate to macromolecules. The water exchange rate, determined from a combined variable-temperature (17)O NMR and EPR study, is two orders of magnitude higher on [Gd(eptpa-bz-NO(2))(H(2)O)](2-) and [Gd(eptpa)(H(2)O)](2-) than on [Gd(dtpa)(H(2)O)](2-) (k(ex)298=150x10(6), 330x10(6), and 3.3x10(6) s(-1), respectively). This is optimal for attaining maximum proton relaxivities for Gd(III)-based, macrocyclic MRI contrast agents. The activation volume of the water exchange, measured by variable-pressure (17)O NMR spectroscopy, evidences a dissociative interchange mechanism for [Gd(eptpa)(H(2)O)](2-) (DeltaV(not equal sign)=(+6.6+/-1.0) cm(3) mol(-1)). In contrast to [Gd(eptpa)(H(2)O)](2-), an interchange mechanism is proved for the macrocyclic [Gd(trita)(H(2)O)](-) (DeltaV (not equal sign)=(-1.5+/-1.0) cm(3) mol(-1)), which has one more CH(2) group in the macrocycle than the commercial MRI contrast agent [Gd(dota)(H(2)O)](-), and for which the elongation of the amine backbone also resulted in a remarkably fast water exchange. When one acetate of DTPA(5-) is substituted by a propionate, the water exchange rate on the Gd(III) complex increases by a factor of 10 (k(ex)298=31x10(6) s(-1)). The [Gd(dptpa)](2-) chelate has no inner-sphere water molecule. The protonation constants of the EPTPA-bz-NO(2) (5-) and DPTPA(5-) ligands and the stability constants of their complexes with Gd(III), Zn(II), Cu(II) and Ca(II) were determined by pH potentiometry. Although the thermodynamic stability of [Gd(eptpa-bz-NO(2))(H(2)O)](2-) is reduced to a slight extent in comparison with [Gd(dtpa)(H(2)O)](2-), it is stable enough to be used in medical diagnostics as an MRI contrast agent. Therefore both this chelate and [Gd(trita)(H(2)O)](-) are potential building blocks for the development of high-relaxivity macromolecular agents.
- Laus, Sabrina,Ruloff, Robert,Toth, Eva,Merbach, Andre E
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p. 3555 - 3566
(2007/10/03)
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- Arginine mimetics as factor Xa inhibitors
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The invention relates generally to a novel type of arginine mimetics which are inhibitors of factor Xa; to pharmaceutical compositions which comprise these mimetics; and to the use of these arginine mimetics for producing compositions for antithrombotic therapy.
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- Substituted N-(3,5-dichlorobenzenesulfonyl)-L-prolyl-phenylalanine analogues as potent VLA-4 antagonists
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A series of substituted N-(3,5-dichlorobenzenesulfonyl)-L-prolyl- and α-methyl-L-prolyl-phenylalanine derivatives was prepared as VLA-4/VCAM antagonists. The compounds showed excellent potency with a wide variety of neutral, polar, electron withdrawing or donating groups on the phenylalanine ring (IC50~1 nM). Heteroaryl ring substitution for phenylalanine was also well tolerated. Pharmacokinetic studies in rat were performed on a representative set of compounds in both series.
- Kopka, Ihor E,Young, David N,Lin, Linus S,Mumford, Richard A,Magriotis, Plato A,MacCoss, Malcolm,Mills, Sander G,Riper, Gail Van,McCauley, Ermengilda,Egger, Linda E,Kidambi, Usha,Schmidt, John A,Lyons, Kathryn,Stearns, Ralph,Vincent, Stella,Colletti, Adria,Wang, Zhen,Tong, Sharon,Wang, Junying,Zheng, Song,Owens, Karen,Levorse, Dorothy,Hagmann, William K
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p. 637 - 640
(2007/10/03)
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- A process for the purification of (S)-4-((3-(dimethylamino)ethyl)-1H-indol-5yl)-methyl)-2-oxazolidinone
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A process for the purification of (S)-4-{[3-(dimethylamino)ethyl]-1H-indol-5yl]-methyl}-2-oxazolidinone and non-solvated, pure (S)-4-{[3-(dimethylamino) ethyl]-1H-indol-5y1]-methyl}-2-oxazolidinone.
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- Synthesis of a novel bifunctional chelating agent for actinium complexation
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A novel bifunctional chelating agent for actinium was synthesized in eight steps. Bimolecular cyclization between an iminodiester and a polyamine was achieved through the action of a molar equivalent of sodium methoxide. (C) 2000 Elsevier Science Ltd.
- Ouadi,Loussouarn,Remaud,Morandeau,Apostolidis,Musikas,Faivre-Chauvet,Gestin
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p. 7207 - 7209
(2007/10/03)
-
- Method for preparing enantiomeric forms of amino alkylaminophenyl propanoic acid
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A process for preparing an enantiomeric form of 2-amino-3-(4-alkylaminophenyl)-propanoic acid of formula (I) or a salt thereof: STR1 in which Alk represents an alkyl radical containing 1 to 2 carbon atoms, from (L)-phenylalanine to obtain the (S)-enantiomer of 2-amino-3-(4-alkylaminophenyl)-propanoic acid, or from (D)-phenylalanine to obtain the (R)-enantiomer of 2-amino-3-(4-alkylaminophenyl)propanoic acid.
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- A novel series of 2,5-substituted tryptamine derivatives as vascular 5HT(1B/1D) receptor antagonists
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The design, synthesis, and activity of a novel series of 2,5- substituted tryptamine derivatives at vascular 5HT(1B)-like receptors is described. Several important auxiliary binding sites of the 5HT(1B)-like receptor have been proposed following various modifications to the 2- substituent and especially to the methylene- or ethylene-linked 5-side chain. Careful design of new molecules based on a proposed pharmacophoric model of the 5HT(1B)-like receptor has resulted in the discovery of ethyl 3-[2- (dimethylamino)ethyl]-5-[2-(2,5-dioxo-1-imidazolidinyl)ethyl]-1H-indole-2- carboxylate (40), a highly potent, silent, competitive, and selective antagonist which shows affinity at the vascular 5HT(1B)-like receptors only. Changes to the size of the 2-ester substituent have a significant effect on affinity at the 5HT(1B)-like receptor and other receptors. Prudent placement of the carbonyl substituent in the heterocycle of the 5-side chain is crucial for good affinity and selectivity over the 5HT(2A) and other receptors. Several key structural and electronic features were identified which are crucial for producing antagonism within a tryptamine-based series. An electron deficient indole ring system appears essential in order to achieve antagonism, and this is achieved by the inclusion of electron-withdrawing groups at the 2-position of the indole ring. The molecule displacement within the receptor resulting from the inclusion of the bulky 2-substituents also enhances antagonism as this results in the removal of the Π electon density of the indole ring from the region of the receptor normally occupied by the indole ring of 5HT. There also appears to be a structural requirement on the side chain incorporating the protonatable nitrogen, and this is achieved by the inclusion of the bulky 2-ester group which neighbors the 3-ethylamine side chain.
- Moloney, Gerard P.,Robertson, Alan D.,Martin, Graeme R.,MacLennan, Steven,Mathews, Neil,Dodsworth, Susan,Sang, Pang Yih,Knight, Cameron,Glen, Robert
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p. 2347 - 2362
(2007/10/03)
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- Computer-Aided Design and Synthesis of 5-Substituted Tryptamines and Their Pharmacology at the 5-HT1D Receptor: Discovery of Compounds with Potential Anti-Migraine Properties
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The design and synthesis of a series of novel 5-substituted tryptamines with pharmacological activity at 5-HT1D and other monoamine receptors is described.Structural modifications of N- and C-linked (prinicipally hydantoin) analogues at the 5-position were synthesized and their pharmacological activities were utilized to deduce significant steric and electrostatic requirements of the 5-HT1D and 5-HT2A receptor subtypes.Conformations of the active molecules were computed which, when overlaid, suggested a pharmacophore hypothesis which was consistent with the affinity and selectivity measured at 5-HT1D and 5-HT2A receptors.This pharmacophore is composed of a protonated amine site, an aromatic site, a hydrophobic pocket, and two hydrogen-bonding sites.A 'selectively site' was also identified which, if occupied, induced selectivity for 5-HT1D over 5-HT2A in this series of molecules.The development and use of the pharmacophore models in compound design is described.In addition, the physicochemical constraints of molecular size and hydrophobicity required for efficient oral absorption are discussed.Utilizing the pharmacophore model in conjuction with the physicochemical constraints of molecular size and log DpH7.4 led to the discovery of 311C90 (6), a new selective 5-HT1D agonist with good oral absorption and potential use in the treatment of migraine.
- Glen, Robert C.,Martin, Graeme R.,Hill, Alan P.,Hyde, Richard M.,Woollard, Patrick M.,et al.
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p. 3566 - 3580
(2007/10/03)
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- Indolyl tetrahydropyridines for treating migraine
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STR1 The present invention is concerned with compounds of formula (I), wherein n is an integer of from 0 to 3: W is a group of formula (i), (ii), or (iii), wherein R is hydrogen or C1-4 alkyl, X is --O--, --S--, --NH--, or --CH2 --, Y is oxygen or sulphur and the chiral center (*) in formula (i) or (ii) is in its (S) or (R) form or is a mixture thereof in any proportions: and Z is a group of formula (iv), (v), or (vi), wherein R1 and R2 are independently selected from hydrogen and C1-4 alkyl and R3 is hydrogen or C1-4 alkyl; and their salts, solvates and physiologically functional derivatives, with processes for their preparation, with medicaments containing them and with their use as therapeutic agents, particularly in the prophylaxis and treatment of migraine.
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- Therapeutic substituted indole compounds and compositions thereof
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The present invention is concerned with compounds of formula (I) STR1 wherein R, R1 and R2 are independently selected from hydrogen and C1-4 alkyl; R3 and R4 are independently selected from hydrogen, C1-6 alkyl (including cycloalkyl) and aryl (wherein the alkyl or aryl group, which latter includes benzyl, is optionally substituted by one or more atoms or groups independently selected from halogen, C1-4 alkyl and aryl), provided R3 benzyl or substituted benzyl when R4 =H; m is an integer of from 0 to 2; n is an integer of from 0 to 3; (W) is a group of formula (i), (ii), (iii), or (iv) STR2 wherein Y is selected from oxygen, methylene and >N--R5, where R5 is hydrogen, C1-4 alkyl, or benzyl, Z and Z' are independently selected from >C=O, >C=S and methylene, and the chiral center * in formula (i) or (ii) is in its (S) or (R) form or is a mixture thereof in any proportions; X is a group selected from aryl (including heteroaryl) xanthenyl dibenzofuranyl which group is optionally substituted; and salts and solvates thereof, the preparation of these compounds, pharmaceutical formulations containing them and their use in medicine, particularly in the treatment of migraine.
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- Backbone polysubstituted chelates for forming a metal chelate-protein conjugate
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New polysubstituted diethylenetriaminepentaacetic acid chelates and protein conjugates of the same are described together with the methods of preparing such compounds. A method of delivering radiolabelled compound of the present invention to a target site while minimizing the distribution of the compound to non-targeted organs or tissues is also disclosed.
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- Efficiency of Second Harmonic Generation from Amino Acids, Peptides, and Polypeptides Carrying Polarizable Aromatic Groups
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The SHG efficiencies of optically active amino acids, their monomeric derivatives, linear and cyclic dipeptides, tripeptides, and polypeptides carrying polarizable groups were tested.Among the 91 samples, L-valine-p-nitroanilide (Val-NA) showed the largest SHG 2ω(urea)>.Val-NA was found to be phase-matchable and transparent down to 420 nm.Monopeptide and dipeptide derivatives of p-nitrophenylalanine also showed large SHG and were transparent down to 420 nm.
- Tokutake, S.,Imanishi, Y.,Sisido, M.
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p. 245 - 258
(2007/10/02)
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- DERIVATIVES OF BETA-ADRENERGIC ANTAGONISTS
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Molecular structures of β-adrenergic antagonists are modified to produce biologically active compounds. The β-antagonists are modified to form molecules of the general structure: STR1 wherein R is most generally R"--OCH 2--, and in some instances is R"--, and R"=an aryl or substituted aryl moiety; R'=--H,--CH 3, or a short chain alkyl moiety; and Y=--OH, or more usually,--OAX or--NHAX, where A=an alkyl, aryl, or aralkyl moiety, and X=a terminal grouping, such as--CH 3,--CF 3 or--(CH 2) n COOH; or AX may be a carrier moiety consisting of a defined peptide or protein. "
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- CHIRAL ANALYSIS OF THE REACTION STAGES IN THE EDMAN METHOD FOR SEQUENCING PEPTIDES
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Chiral isothiocyanate reagents suitable for 'Edman sequencing' have been synthesised and used to assess the chiral features of individual stages in the Edman method.Using h.p.l.c. analysis of the diastereoisomeric thiohydantoins obtained, it has been deduced that the cyclisation and cleavage of thiazolinone step is the likely source of racemisation of the chiral centre derived from the N-terminal amino acid.
- Davies, John S.,Mohammed, Karim A.
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p. 1723 - 1728
(2007/10/02)
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