- Plasminogen activator inhibitor-1 inhibitors and methods of use thereof to modulate lipid metabolism
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The invention relates to plasminogen activator-1 (PAI-1) inhibitor compounds and uses thereof in the treatment of any disease or condition associated with elevated PAI-1. The invention includes, but is not limited to, the use of such compounds to modulate lipid metabolism and treat conditions associated with elevated PAI-1, cholesterol, or lipid levels.
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Page/Page column 68
(2015/09/22)
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- Broad spectrum antibiotic arylomycin analogs
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Arylomycin analogs are provided, wherein the analogs can have broad spectrum bioactivity. Resistance to the antibiotic bioactivity of natural product arylomycin in a range of pathogenic bacterial species has been found to depend upon single amino acid mutations at defined positions of bacterial Signal Peptidases (SPases), wherein the presence of a proline residue confers arylomycin resistance. Arylomycin analogs are provided herein that can overcome that resistance and provide for a broader spectrum of antibiotic bioactivity than can natural product arylomycins such as arylomycin A2. Methods for determining if a bacterial strain is susceptible to narrow spectrum arylomycin antibiotics, or if a broad spectrum analog is required for treatment, is provided. Pharmaceutical compositions and methods of treatment of bacterial infections, and methods of synthesis of arylomycin analogs, are provided.
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Page/Page column 131
(2015/12/30)
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- Quantitative insight into the design of compounds recognized by the L-type amino acid transporter 1 (LAT1)
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L-Type amino acid transporter 1 (LAT1) is a transmembrane protein expressed abundantly at the blood-brain barrier (BBB), where it ensures the transport of hydrophobic acids from the blood to the brain. Due to its unique substrate specificity and high expression at the BBB, LAT1 is an intriguing target for carrier- mediated transport of drugs into the brain. In this study, a comparative molecular field analysis (CoMFA) model with considerable statistical quality (Q2=0.53, R2=0.75, Q2 SE=0.77, R2 SE=0.57) and good external predictivity (CCC=0.91) was generated. The model was used to guide the synthesis of eight new prodrugs whose affinity for LAT1 was tested by using an in situ rat brain perfusion technique. This resulted in the creation of a novel LAT1 prodrug with l-tryptophan as the promoiety; it also provided a better understanding of the molecular features of LAT1-targeted high-affinity prodrugs, as well as their promoiety and parent drug. The results obtained will be beneficial in the rational design of novel LAT1-binding prodrugs and other compounds that bind to LAT1.
- Ylikangas, Henna,Malmioja, Kalle,Peura, Lauri,Gynther, Mikko,Nwachukwu, Emmanuel O.,Lepp?nen, Jukka,Laine, Krista,Rautio, Jarkko,Lahtela-Kakkonen, Maija,Huttunen, Kristiina M.,Poso, Antti
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supporting information
p. 2699 - 2707
(2015/02/02)
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- Synthesis and biological characterization of arylomycin B antibiotics
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Antibiotics are virtually always isolated as families of related compounds, but the evolutionary forces underlying the observed diversity are generally poorly understood, and it is not even clear whether they are all expected to be biologically active. Th
- Roberts, Tucker C.,Smith, Peter A.,Romesberg, Floyd E.
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experimental part
p. 956 - 961
(2011/07/30)
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- Intramolecular suzuki-miyaura reaction for the total synthesis of signal peptidase inhibitors, arylomycins A2and B2
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Development of the total syntheses of arylomycins A1 and B 2 is detailed. Key features of our approach include 1) formation of 14-membered meta, meta-cyclophane by an intramolecular Suzuki-Miyaura reaction; 2) incorporation of N-Me-4-hydroxyphenylglycine into the cyclization precursor, which avoids the late-stage low-yielding N-methylation step; 3) segment coupling of a fully elaborated peptide side chain to the macrocycle, which makes the synthesis highly convergent. Overall, arylomycin A2 was obtained in 13 steps from L-Tyr for the longest linear sequence, in 13% overall yield. Arylomycin B2 was synthesized in 10 steps from L-3-nitro-Tyr, in 10% overall yield.
- Dufour, Jeremy,Neuville, Luc,Zhu, Jieping
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scheme or table
p. 10523 - 10534
(2010/11/04)
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- Chemoselective nitration of phenols with iert-butyl nitrite in solution and on solid support
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test-Butyl nitrite was identified as a safe and chemoselective nitrating agent that provides preferentially mononltro derivatives of phenolic substrates In the presence of potentially competitive functional groups. On the basis of our control experiments, we propose that the reaction proceeds through the formation of O-nltrosyl Intermediates prior to C-nitration via homolysis and oxidation. The reported nitration method Is compatible with tyroslne-containlng peptides on solid support In the synthesis of fluorogenic substrates for characterization of proteases.
- Koley, Dlpankar,Colon, Olvia C.,Savlnov, Sergey N.
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supporting information; experimental part
p. 4172 - 4175
(2009/12/30)
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- Plasminogen Activator Inhibitor-1 Inhibitors And Methods Of Use Thereof To Modulate Lipid Metabolism
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The invention relates to plasminogen activator-1 (PAI-1) inhibitor compounds and uses thereof in the treatment of any disease or condition associated with elevated PAI-1. The invention includes, but is not limited to, the use of such compounds to modulate lipid metabolism and treat conditions associated with elevated PAI-1, cholesterol, or lipid levels.
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- Preparation of phosphatase inhibitors
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Disclosed are compounds of the Formula I and pharmaceutically acceptable salts and prodrugs thereof, wherein A, B, R1, R2, R3, R4 and R5 are as defined in the specification. Such compounds are tyrosine phosphatase inhibitors and useful in the treatment or prevention of Type II Diabetes Mellitus. Also encompassed by the invention are formulations comprising the noted compounds, processes for preparing such compounds, a method for treating or preventing Type II Diabetes Mellitus.
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- Depsipeptide derivatives, production thereof and use thereof
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wherein A is benzyl group which has suitable substituent(s) or phenyl group which may have suitable substituent(s), Aa is benzyl group which may have suitable substituent(s) or phenyl group which may have suitable substituent(s), B and D are each lower alkyl, C is hydrogen or lower alkyl, and a pharmaceutically acceptable salt thereof. The compound or a salt thereof of the present invention has excellent parasiticidal activities as an anthelmintic agent for animals and human bodies.
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