- Synthesis of desmosine-containing cyclic peptide for the possible elucidation of elastin crosslinking structure
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Elastin is a vital extracellular matrix protein, which is known for providing elasticity in numerous tissues. It is formed by the self-assembly and subsequent crosslinking of elastin precursor, tropoelastin. Two tetrafunctional, pyridinium-based amino acids desmosine and isodesmosine are exclusively found in elastin and play an important role as crosslinkers. Structural elucidation of elastin has eluded scientists to date, owing to the highly cross-linked structure and insoluble nature. Therefore, in this study, we aimed to synthesize a desmosine-containing cyclic peptide as a partial elastin mimic, in order to eventually facilitate the elucidation of the crosslinking pattern of elastin by mass spectrometric analysis.
- Ogawa, Keita,Hayashi, Takahiro,Lin, Yong Y.,Usuki, Toyonobu
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p. 3838 - 3847
(2017/06/13)
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- Synthesis of l-indospicine, [5,5,6-2H3]-l-indospicine and l-norindospicine
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Indospicine is a non-proteogenic amino acid that accumulates as the free amino acid in livestock grazing Indigofera plant species and causes both reproductive losses and hepatotoxic effects. An efficient synthetic route to l-indospicine from l-homoserine lactone is described. The methodology is applicable for the synthesis of both deuterium labelled isotopomers and structural analogues for utilisation in biological studies. The key steps are a zinc mediated Barbier reaction with acrylonitrile and a Pinner reaction that together introduce the target amidine moiety.
- Lang, Cheng-Shan,Wong, Siew-Hoon,Chow, Sharon,Challinor, Victoria L.,Yong, Ken W. L.,Fletcher, Mary T.,Arthur, Dionne M.,Ng, Jack C.,De Voss, James J.
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p. 6826 - 6832
(2016/07/23)
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- Light-mediated deoxygenation of alcohols with a dimeric gold catalyst
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A new protocol for the reductive deoxygenation of primary alcohols was explored. This photo-mediated method combines a novel approach to bromination of alcohols merged with the powerful reducing capability of [Au2(dppm)2]Cl2 [dppm = 1,1-bis(diphenylphosphino)methane] as a photoredox catalyst. The highly efficient methods discussed are marked by the use of UVA light-emitting diodes, which have significantly reduced reaction times and lowered setup cost.
- McCallum, Terry,Slavko, Ekaterina,Morin, Mathieu,Barriault, Louis
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- 4-((R)-2-{[6-((S)-3-Methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carbonyl]amino}-3-phosphonopropionyl)piperazine-1-carboxylic Acid Butyl Ester (ACT-246475) and Its Prodrug (ACT-281959), a Novel P2Y12 Receptor Antagonist with a Wider Therapeutic Window in the Rat Than Clopidogrel
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Recent post hoc analyses of several clinical trials with P2Y12 antagonists showed the need for new molecules being fully efficacious as antiplatelet agents and having a reduced propensity to cause major bleeding. We have previously reported the discovery of the 2-phenylpyrimidine-4-carboxamide analogs as P2Y12 antagonists with nanomolar potency in the disease-relevant platelet aggregation assay in human plasma. Herein we present the optimization steps that led to the discovery of clinical candidate ACT-246475 (30d). The key step was the replacement of the carboxylic acid functionality by a phosphonic acid group which delivered the most potent molecules of the program. In addition, low in vivo clearance in rat and dog was achieved for the first time. Since the bioavailability of 30d was low in rat and dog, we developed the bis((isopropoxycarbonyl)oxy)methyl ester prodrug (ACT-281959, 45). Compound 30d showed efficacy in the rat ferric chloride thrombosis model when administered intravenously as parent or orally as its prodrug 45. Moreover, 30d displays a wider therapeutic window as compared to clopidogrel in the rat surgical blood loss model.
- Caroff, Eva,Hubler, Francis,Meyer, Emmanuel,Renneberg, Dorte,Gnerre, Carmela,Treiber, Alexander,Rey, Markus,Hess, Patrick,Steiner, Beat,Hilpert, Kurt,Riederer, Markus A.
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p. 9133 - 9153
(2015/12/23)
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- An access to aza-Freidinger lactams and E-locked analogs
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Freidinger lactams, possessing a peptide bond configuration locked to Z, are important key elements of conformationally restricted peptidomimetics. In the present work, the CαHi+1 unit has been replaced by N, leading to novel aza-Fre
- Ottersbach, Philipp A.,Schmitz, Janina,Schnakenburg, Gregor,Gütschow, Michael
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p. 448 - 451
(2013/04/11)
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- PHOSPHONIC ACID DERIVATES AND THEIR USE AS P2Y12 RECEPTOR ANTAGONISTS
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The invention relates to 2-phenyl-pyrimidine derivatives containing a phosphonic acid motif and their use as P2Y12 receptor antagonists in the treatment and/or prevention of peripheral vascular, of visceral-, hepatic- and renal-vascular, of cardiovascular and of cerebrovascular diseases or conditions associated with platelet aggregation, including thrombosis in humans and other mammals. (I).
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Page/Page column 68
(2009/07/03)
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- ETHER DERIVATIVE
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The present invention relates to an ether derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof wherein each symbol is as defined in the description, and an ether derivative represented by the formula (III), a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof wherein each symbol is as defined in the description; a pharmaceutical composition containing the ether derivative; and a package containing the pharmaceutical composition and a description of use thereof. A pharmaceutical composition of the present invention, which contains this compound of the present invention has a superior anti-inflammatory and analgesic activity and is useful as various pharmaceutical agents such as an anti-inflammatory agent, an analgesic, a therapeutic agent for inflammatory bowel disease, a therapeutic agent for pollakiuria and/or incontinentia, a therapeutic agent for asthma and the like.
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Page/Page column 40
(2008/06/13)
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- Use of synthetic glycolipids as universal adjuvants for vaccines against cancer and infectious diseases
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The present invention relates to methods and compositions for augmenting an immunogenicity of an antigen in a mammal, comprising administering said antigen together with an adjuvant composition that includes a synthetic glycolipid compound of Formula I, a
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Page/Page column 15; 19
(2008/06/13)
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- The C-glycoside analogue of the immunostimulant α-galactosylceramide (KRN7000): Synthesis and striking enhancement of activity
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Which source provides the better drug? The fully synthetic C-glycoside I (Y=CH2) is about 1000 times more potent against malaria in mice than the corresponding O-glycoside (Y=O), which is derived from a natural product and itself known to show remarkable activity against a wide range of diseases. The results of comparative biological assays emphasize the potential of C-glycosides as therapeutic agents.
- Yang, Guangli,Schmieg, John,Tsuji, Moriya,Franck, Richard W.
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p. 3818 - 3822
(2007/10/03)
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- SYNTHETIC C-GLYCOLIPID AND ITS USE FOR TREATING CANCER INFECTIOUS DISEASES AND AUTOIMMUNE DISEASES
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The invention is directed to compounds of formula (I) wherein X is O, OR NH; R' is a hydrocarbon chain; R and are hydrogen, OH or a monosaccharide; R is hydrogen or a monosaccharide; Q' is optionally present and may be a C1-10 hydrocarbon; X' i
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- Inhibition of trypanothione reductase by substrate analogues.
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Trypanothione reductase (TR) catalyzes the NAPDH-dependent reduction of the spermidine-glutathione conjugate trypanothione, an antioxidant found in Trypanosomatid parasites. TR plays an essential role in the parasite's defense against oxidative stress and
- Garrard,Borman,Cook,Pike,Alberg
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p. 3639 - 3642
(2007/10/03)
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