- Synthesis of Shld Derivatives, Their Binding to the Destabilizing Domain, and Influence on Protein Accumulation in Transgenic Plants
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A series of 35 analogues of Shld with modifications in the A-residue and the C-residues were prepared and investigated for binding to FKBP and GFP accumulation in transgenic plants. The modifications investigated explored variations that were supposedly i
- J?rgensen, Frederik Pr?stholm,Madsen, Daniel,Meldal, Morten,Olsen, Jacob Valdbj?rn,Petersen, Morten,Granh?j, Jeppe,Bols, Mikael
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p. 5191 - 5216
(2019/05/28)
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- 2-ARYLSULFONAMIDO-N-ARYLACETAMIDE DERIVATIZED STAT3 INHIBITORS
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The present disclosure provides pharmaceutical compositions comprising 2-arylsulfonamido-N-arylacetamide derivatized Stat3 inhibitors and certain pharmaceutically acceptable salts thereof, and methods of their use.
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Paragraph 00342
(2018/08/20)
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- Heterocyclic core analogs of a direct thrombin inhibitor
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Thrombin is a serine protease that plays a key role in blood clotting. Pyrrolidine 1 is a potent thrombin inhibitor discovered at Merck several years ago. Seven analogs (2-8) of 1 in which the pyrrolidine core was replaced with various heterocycles were p
- Blizzard, Timothy A.,Singh, Sanjay,Patil, Basanagoud,Chidurala, Naresh,Komanduri, Venukrishnan,Debnath, Samarpita,Belyakov, Sergei,Crespo, Alejandro,Struck, Alice,Kurtz, Marc,Wiltsie, Judyann,Shen, Xun,Sonatore, Lisa,Arocho, Marta,Lewis, Dale,Ogletree, Martin,Biftu, Tesfaye
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p. 1111 - 1115
(2014/03/21)
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- Chiral separation of the clinically important compounds fucose and pipecolic acid using ce: Determination of the most effective chiral selector
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In this study, simple electrophoretic methods were developed for the chiral separation of the clinically important compounds fucose and pipecolic acid. In recent years, these analytes, and particularly their individual enantiomers, have attracted considerable attention due to their role in biological functions and disorders. The detectability and sensitivity of pipecolic acid and fucose were improved by reacting them with fluorenylmethyloxycarbonyl chloride (FMOC-Cl) and 5-amino-2-naphthalene-sulfonic acid (ANSA), respectively. The enantioseparation conditions were optimized by initially investigating the type of the chiral selector. Different chiral selectors, such as polymeric surfactants and cyclodextrins, were used and the most effective ones were determined with regard to resolution and analysis time. A 10-mM β-cyclodextrin was able to separate the enantiomers of ANSA-DL-fucose and the polymeric surfactant poly(sodium N-undecanoyl-LL-leucine-valinate) was able to separate the enantiomers of FMOC-DL-pipecolic acid, with resolution values of 3.45 and 2.78, respectively. Additional parameters, such as the concentration and the pH of the background electrolyte (BGE), the concentration of the chiral selector, and the addition of modifiers were examined in order to optimize the separations. The addition of the chiral ionic liquid D-alanine tert-butyl ester lactate into the BGE was also investigated, for the first time, in order to improve resolution of the enantiomers. 2013 Wiley Periodicals, Inc.
- Hadjistasi, Christoforos A.,Stavrou, Ioannis J.,Stefan-Van Staden, Raluca-Ioana,Aboul-Enein, Hassan Y.,Kapnissi-Christodoulou, Constantina P.
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p. 556 - 560
(2013/09/12)
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- PIPECOLATE-DIKETOAMIDES FOR TREATMENT OF PSYCHIATRIC DISORDERS
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The present invention relates to compounds having a pipecolate diketoamide scaffold, pharmaceutically acceptable salts of these compounds and pharmaceutical compositions containing at least one of these compounds together with pharmaceutically acceptable carrier, excipient and/or diluents. Said pipecolate diketoamide compounds can be used for prophylaxis and/or treatment of psychiatric disorders and neurodegenerative diseases, disorders and conditions.
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Page/Page column 41
(2013/07/05)
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- Pipecolate-diketoamides for treatment of psychiatric disorders
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The present invention relates to compounds having a pipecolate diketoamide scaffold, pharmaceutically acceptable salts of these compounds and pharmaceutical compositions containing at least one of these compounds together with pharmaceutically acceptable
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Paragraph 0111
(2013/07/19)
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- THROMBIN INHIBITORS
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Compounds of the invention are useful in inhibiting thrombin and associated thrombotic occlusions having the following structure: (I) or a pharmaceutically acceptable salt thereof, wherein Q is CH2, NR4, O, S, S(O) or S(O2
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Page/Page column 23
(2013/10/21)
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- Evaluation of synthetic FK506 analogues as ligands for the FK506-binding proteins 51 and 52
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The FK506-binding proteins (FKBP) 51 and 52 are cochaperones that modulate the signal transduction of steroid hormone receptors. Both proteins have been implicated in prostate cancer. Furthermore, single nucleotide polymorphisms in the gene encoding FKBP51 have been associated with a variety of psychiatric disorders. Rapamycin and FK506 are two macrocyclic natural products that bind to these proteins indiscriminately but with nanomolar affinity. We here report the cocrystal structure of FKBP51 with a simplified α-ketoamide analogue derived from FK506 and the first structure-activity relationship analysis for FKBP51 and FKBP52 based on this compound. In particular, the tert-pentyl group of this ligand was systematically replaced by a cyclohexyl ring system, which more closely resembles the pyranose ring in the high-affinity ligands rapamycin and FK506. The interaction with FKBPs was found to be surprisingly tolerant to the stereochemistry of the attached cyclohexyl substituents. The molecular basis for this tolerance was elucidated by X-ray cocrystallography.
- Gopalakrishnan, Ranganath,Kozany, Christian,Gaali, Steffen,Kress, Christoph,Hoogeland, Bastiaan,Bracher, Andreas,Hausch, Felix
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supporting information; experimental part
p. 4114 - 4122
(2012/06/30)
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- Total synthesis of the antifungal depsipeptide petriellin A
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We report the solid-phase total synthesis of the antifungal highly modified cyclic depsipeptide petriellin A. The synthesis confirms earlier reports on the absolute configuration of the natural product. The solid-phase approach resulted in a protected lin
- Sleebs, Marianne M.,Scanlon, Denis,Karas, John,Maharani, Rani,Hughes, Andrew B.
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p. 6686 - 6693
(2011/10/18)
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- Biosynthesis of pipecolic acid by RapL, a lysine cyclodeaminase encoded in the rapamycin gene cluster
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Rapamycin, FK506, and FK520 are immunosuppressant macrolactone natural products comprised of predominantly polyketide-based core structures. A single nonproteinogenic pipecolic acid residue is installed into the scaffold by a nonribosomal peptide synthetase that also performs the subsequent macrocyclization step at the carbonyl group of this amino acid. It has been assumed that pipecolic acid is generated from lysine by the cyclodeaminases RapL/FkbL. Herein we report the heterologous overexpression and purification of RapL and validate its ability to convert L-lysine to L-pipecolic acid by a cyclodeamination reaction that involves redox catalysis. RapL also accepts L-ornithine as a substrate, albeit with a significantly reduced catalytic efficiency. Turnover is presumed to encompass a reversible oxidation at the α-amine, internal cyclization, and subsequent re-reduction of the cyclic Δ1-piperideine-2-carboxylate intermediate. As isolated, RapL has about 0.17 equiv of tightly bound NAD+, suggesting that the enzyme is incompletely loaded when overproduced in E. coli. In the presence of exogenous NAD+, the initial rate is elevated 8-fold with a K m of 2.3 μM for the cofactor, consistent with some release and rebinding of NAD+ during catalytic cycles. Through the use of isotopically labeled substrates, we have confirmed mechanistic details of the cyclodeaminase reaction, including loss of the α-amine and retention of the hydrogen atom at the α-carbon. In addition to the characterization of a critical enzyme in the biosynthesis of a medically important class of natural products, this work represents the first in vitro characterization of a lysine cyclodeaminase, a member of a unique group of enzymes which utilize the nicotinamide cofactor in a catalytic manner.
- Gatto Jr., Gregory J.,Boyne II, Michael T.,Kelleher, Neil L.,Walsh, Christopher T.
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p. 3838 - 3847
(2007/10/03)
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- Solid-phase synthesis and utilization of side-chain reactive unnatural amino acids
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Alkylation of the benzophenone imine of glycine Wang resin with α,ω-dihaloalkanes yielded valuable reactive intermediates. These racemic ω-chloro or ω-bromo intermediates were converted to α-amino acids containing diverse side-chain functionalities (e.g.
- O'Donnell, Martin J.,Alsina, Jordi,Scott, William L.
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p. 8403 - 8406
(2007/10/03)
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- PEPTIDE DERIVATIVES
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The invention concerns pharmaceutically useful peptide derivatives of the formula (I), P-AA I -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -AA 7 -AA 8 -Q, in which P, AA 1, AA 2, AA 3 , AA 4, AA 5, AA 6, AA 7, AA 8, and Q have the various meanings defined herein and their pharmaceutically accentable salts, and pharmaceutical compositions containing them. The novel peptide derivatives are of value in treating MHC class II dependent T-cell mediated autoimmune or inflammatory diseases, such as rheumatoid arthritis. The invention further concerns processes for the manufacture of the novel peptide derivatives and the use of the compounds in medical treatment.
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- Brain-targeted chemical delivery of [Leu2, Pip3]-TRH: Synthesis and biological evaluation
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A chemical targeting system for [Leu2, Pip3]-TRH (Gln,Leu,Pip) was synthesized in order to allow its specific delivery to the central nervous system (CNS). Sequential metabolism of the obtained 'packaged' chemical delivery system, (CDS), DHT-Pro-Pro-Gln-Leu-Pip-OCh, should yield a 'locked- in' precursor following the oxidative conversion of the dihydrotrigonellyl (DHT) to the trigonellyl (T+) moiety, followed by removal of the cholesteryl function and cleavage of the T+-Pro-Pro by prolyl endopeptidase. The antagonism of barbiturate-induced sleeping time was used to assess the activity of the CDS. The sleeping time after administration of vehicle and [Leu2]-TRH was 100.5 ± 6.3 min, and 78.2 ± 4.7 min, respectively. The [Leu2, Pip3]-TRH-CDS showed a significant decrease in sleeping time (58.2 ± 3.4 min) compared to the vehicle or [Leu2]-TRH. These results indicate successful brain delivery of the precursor construct, and an effective release of the active GlnLeuPip in the brain. (C) 2000 Elsevier Science Ltd.
- Yoon, Sung-Hwa,Wu, Jiaxiang,Wu, Whei-Mei,Prokai, Laszlo,Bodor, Nicholas
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p. 1059 - 1063
(2007/10/03)
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- Peptide derivatives useful in treating autoimmune diseases
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PCT No. PCT/GB97/00438 Sec. 371 Date Aug. 20, 1998 Sec. 102(e) Date Aug. 20, 1998 PCT Filed Feb. 18, 1997 PCT Pub. No. WO97/31023 PCT Pub. Date Aug. 28, 1997The invention concerns pharmaceutically useful peptide derivatives of the formula (I): P-R1-R2-R3-R4, in which P, R1, R2, R3, and R4 have the various meanings defined herein, and their pharmaceutically acceptable salts, and pharmaceutical compositions containing them. The novel peptide derivatives are of value in treating MHC class II dependent T-cell mediated autoimmune or inflammatory diseases, such as rheumatoid arthritis. The invention further concerns processes for the manufacture of the novel peptide derivatives and the use of the compounds in medical treatment.
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- Use of N-Fmoc Amino Acid Chlorides and Activated 2-(Fluorenylmethoxy)-5(4H)-oxazolones in Solid-Phase Peptide Synthesis. Efficient Syntheses of Highly N-Alkylated Cyclic Hexapeptide Oxytocin Antagonists Related to L-365,209
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Fmoc amino acid chlorides have been shown to be useful reagents in the solid-phase synthesis of hexapeptides containing up to four sequential secondary amino acids.The oxytocin antagonist cyclo-(D-Phe-Ile-D-Pip-Pip-D-(N-Me)Phe-Pro) (1) was prepared in 70p
- Perlow, Debra S.,Erb, Jill M.,Gould, Norman P.,Tung, Roger D.,Freidinger, Roger M.,et al.
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p. 4394 - 4400
(2007/10/02)
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- Anti-thrombotic peptide and pseudopeptide derivatives
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Disclosed are novel peptide and pseudopeptide derivatives and phrmaceutical compositions thereof that inhibit platelet aggregation and thrombus formation in mammalian blood.
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- Novel arginine, glycine, aspartic acid derivatives as platelet-aggregation inhibitors
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Disclosed are novel amino acid derivatives of the formula: STR1 wherein X is H, amidino or STR2 Y is H, amino or STR3 Z is STR4 OR1 or a naturally occurring L-amino acid, bounded to the carbon atom at the α-amino position; R is alkyl, aryl or aralkyl; R1 and R2 are independently H, alkyl, aryl, aralkyl or allyl; m is 1 through 5; n is 0 through 4; and pharmaceutically acceptable salts thereof, that inhibit platelet aggregation and thrombus formation in mammalian blood.
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- 9-Fluorenylmethyl Pentafluorophenyl Carbonate as a Useful Reagent for the Preparation of N-9-Fluorenylmethyloxycarbonylamino Acids and their Pentafluorophenyl Esters
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9-Fluorenylmethyl pentafluorophenyl carbonate is a useful reagent for the efficient, side reaction-free introduction of N-9-fluorenylmethyloxycarbonyl protecting group into amino acids and for the subsequent preparation of their pentafluorophenyl esters.Some new compounds of both types are described.
- Schoen, Istvan,Kisfaludy, Lajos
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p. 303 - 305
(2007/10/02)
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