- Investigation of the Stereoselective Synthesis of the Indane Dimer PH46A, a New Potential Anti-inflammatory Agent
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PH46A, belonging to a class of 1,2-Indane dimers, has been developed by our research group as a potential therapeutic agent for the treatment of inflammatory and autoimmune diseases. The initial synthetic route to PH46A gave a low overall yield, due in la
- Cumming, Graham R.,Zhang, Tao,Scalabrino, Gaia,Frankish, Neil,Sheridan, Helen
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Read Online
- Design, synthesis and structure?activity relationship studies of GPR40 agonists containing amide linker
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Free fatty acid receptor 1 (FFAR1/GPR40) attracted significant attention as a potential target for developing novel antidiabetic drugs because of its unique mechanism in glucose homeostasis. Several reports have expressed concerns about central nervous system (CNS) penetration of GPR40 agonists, which is possibly attributed to their high lipophilicity and low total polar surface area. Herein, we report our efforts to improve the physicochemical properties and pharmacokinetic profiles of LY2881835, a GPR40 agonist that had undergone Phase I clinical trial, through a series of structural optimizations. We identified an orally efficacious compound, 15k, which possessed increased plasma exposure, prolonged half-life and reduced CNS exposure and liver to plasma distribution ratio compared with LY2881835. 15k is a potentially valuable lead compound in the development of safe and efficacious GPR40-targeted drugs to treat type 2 diabetes mellitus.
- Chen, Tingting,Ning, Mengmeng,Ye, Yangliang,Wang, Kai,Leng, Ying,Shen, Jianhua
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Read Online
- Novel nicotinoid structures for covalent modification of wood: An environmentally friendly way for its protection against insects
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Timber is constantly exposed to environmental influences under outdoor conditions which limits its lifetime and usability. In order to counteract the damaging processes caused by insects, we have developed a novel and more environmentally friendly method to protect wood materials via covalent modification by organic insecticides. Starting with an important class of synthetic insecticides which are derived from the natural insecticide nicotine, various new carboxylic acid derivatives of imidacloprid were made accessible. These activated neonicotinoids were utilized for the chemical modification of wood hydroxy groups. In contrast to conventional wood preservation methods in which biocides are only physically bound to the surface for a limited time, the covalent fixation of the preservative guarantees a permanent effect against wood pests, demonstrated in standardized biological tests. Additionally, the environmental interaction caused by non-bound neonicotinoids is significantly reduced, since both, a smaller application rate is required and leaching of the active ingredient is prevented. By minimizing the pest infestation, the lifetime of the material increases while preserving the natural appearance of the material.
- Acker, Sophie,Kaufmann, Dieter E.,Namyslo, Jan C.,Plarre, Rudy,S?ftje, Martin
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p. 15726 - 15733
(2020/05/13)
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- Acid-Stable Ester Linkers for the Solid-Phase Synthesis of Immobilized Peptides
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A series of N-terminally Fmoc-protected linkers of the general formula Fmoc-X?CO?O?Y?COOH have been prepared, where X is ?NH?CH2?CH2- or -p-(aminomethyl)phenyl- and Y is ?(CH2)n? (n is 1 or 4) or -p-(methyl)phenyl-. These linkers can easily be covalently attached via their C-terminal carboxyl group to a resin bearing a free amino group. After cleavage of the N-terminal Fmoc group, the linkers can be extended by standard solid-phase peptide synthesis techniques. These ester linkers are acid-stable and resistant to the base-mediated diketopiperazine formation that often occurs during the synthesis of ester-bound peptides; they are stable at neutral pH in aqueous buffers for days but can be effectively cleaved with 0.1 m NaOH or aq. ammonia within minutes or hours, respectively. These properties make these ester handles well suited for use as linkers for the solid-phase peptide synthesis of immobilized peptides when the stable on-resin immobilization of the peptides and the testing of their biological properties in aqueous buffers at neutral pH are necessary.
- Budě?ínsky, Milo?,Jirá?ek, Ji?í,Mitrová, Katarína,Pícha, Jan
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p. 1297 - 1306
(2020/07/04)
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- 3-(1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE DERIVATIVES AND USES THEREOF
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The present disclosure provides a compound of Formula (I′): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein R1, R2, Rx, X1, n, n1, and q are as defined herein, and methods of making and using same.
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Paragraph 0857; 0859
(2019/03/08)
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- A class of GPR40 agonist compounds with amide structure, and uses thereof
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The present invention relates to a class of amide compounds with a novel structure, and a pharmaceutical composition thereof, wherein the structure of the amide compound is represented by a general formula (I). According to the present invention, the amide compound (I) can regulate GPR40 activity, and can be used for GPR40 activity related diseases such as diabetes and metabolic syndrome. The formula I is defined in the specification.
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Paragraph 0115; 0116; 0118; 0121
(2019/05/02)
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- Picolinamide oligomers, preparation method and applications thereof
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The invention belongs to the technical field of membrane separation, and more specifically relates to picolinamide oligomers, a preparation method and applications thereof. The picolinamide oligomerscomprise the following characteristics: 1. the oligomers
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Paragraph 0047; 0052
(2018/08/28)
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- Electrophilic Zinc Homoenolates: Synthesis of Cyclopropylamines from Cyclopropanols and Amines
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Metal homoenolates, produced via C-C bond cleavage of cyclopropanols, have been extensively investigated as nucleophiles for the synthesis of β-substituted carbonyl derivatives. Herein, we demonstrate that zinc homoenolates can react as carbonyl-electrophiles in the presence of nucleophilic amines to yield highly valuable trans-cyclopropylamines in good yields and high diastereoselectivities. GSK2879552, a lysine demethylase 1 inhibitor currently in clinical trials for the treatment of small cell lung carcinoma, was synthesized using this strategy.
- Mills, L. Reginald,Barrera Arbelaez, Luis Miguel,Rousseaux, Sophie A. L.
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p. 11357 - 11360
(2017/08/30)
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- New calix[4]arene-cored peripherally functionalized dendrimers: Synthesis and conformational characteristics
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Abstract New calixarene-based dendrimers, containing calix[4]arene as the core and different generations of Fréchet-type poly(benzyl ether) dendrons as building blocks, which possess either Br-atoms or COOtBu groups at their surface were synthe
- Paraskevopoulos, Georgios,Alivertis, Dimitrios,Theodorou, Vassiliki,Skobridis, Konstantinos
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p. 593 - 603
(2015/06/02)
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- Metallocene compounds and labeled molecules comprising the same for in vivo imaging.
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The present invention concerns compounds and methods of labeling peptides or other molecules with 18F or 19F or any other suitable radionuclide of use, for example, in PET or NMR in vivo imaging. A targeting molecule such as a protei
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Paragraph 0107; 0108; 0109; 0110; 0111; 0112; 0113
(2014/09/29)
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- COMPOUNDS
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The invention relates to new derivatives of 5-aminolevulinic acid (5-ALA) and their use as photosensitizing agents. In particular, it relates to compounds of general formula I and their pharmaceutically acceptable salts, to methods for preparing such compounds and their medical and cosmetic use, for example in methods of photodynamic therapy and diagnosis: wherein R1 represents a hydrogen atom or an optionally substituted alkyl or cycloalkyl group; R2, each of which may be the same or different, represents a hydrogen atom or an optionally substituted alkyl group; and X is a linking group.
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Page/Page column 43
(2014/02/16)
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- Peroxisome proliferator-activated receptor agonists with phenethylphenylphthalimide skeleton derived from thalidomide-related liver X receptor antagonists: Relationship between absolute configuration and subtype selectivity
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Introduction of an alkylcarboxylic acid unit, which is a partial structure of endogenous peroxisome proliferator-activated receptor (PPAR) ligands, into a phenethylphenylphthalimide skeleton, which possesses liver X receptor (LXR) antagonistic activity, afforded novel PPAR ligands. The results of structure-activity relationship analysis and docking studies led us to the potent PPAR agonists 13c-e. The absolute configuration of 13c-e affects the PPAR subtype selectivity.
- Motoshima, Kazunori,Ishikawa, Minoru,Hashimoto, Yuichi,Sugita, Kazuyuki
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experimental part
p. 3156 - 3172
(2011/06/26)
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- D2 ANTAGONISTS, METHODS OF SYNTHESIS AND METHODS OF USE
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Provided are D2 or D3 antagonist compounds and pharmaceutical compositions of formula I and pharmaceutically acceptable salts thereof, or isomers thereof, wherein R1, R2 and R3 are as defined herein. The invention further comprises methods for making the compounds of the invention and methods for the treatment of conditions mediated by the dopamine D2 or D3 receptor from the compounds of the invention.
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Page/Page column 121-122
(2012/01/06)
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- Expedient solution-phase synthesis and NMR studies of arylopeptoids
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The development of a highly convenient and efficient protocol for iterative solution-phase synthesis of shorter oligomers of para-and meta-arylopeptoids is described. Peptide coupling methods for accessing longer oligomers were studied: use of the new cou
- Hjelmgaard, Thomas,Faure, Sophie,Staerk, Dan,Taillefumier, Claude,Nielsen, John
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experimental part
p. 4121 - 4132
(2011/09/20)
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- Dendritically encapsulated, water-soluble Fe4S4: Synthesis and electrochemical properties
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Amphiphilic, Fe4S4 cluster core dendrimers can be prepared via ligand exchange with dendrons containing carboxylic acid peripheral groups and a thiol focal group. These amphiphilic dendrons are more susceptible to oxidative disulfide
- Sharma, Anil K.,Kim, Namjin,Cameron, Christopher S.,Lyndon, Matthew,Gorman, Christopher B.
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experimental part
p. 5072 - 5078
(2010/08/21)
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- Inhibitors of Histone Deacetylase
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The present invention relates to a novel class of compounds. These compounds can inhibit histone deacetylase and are suitable for use in selectively inducing terminal differentiation, and arresting cell growth and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells. Thus, the compounds of the present invention are useful in treating a patient having a tumor characterized by proliferation of neoplastic cells. The compounds of the invention may also be useful in the prevention and treatment of TRX-mediated diseases, such as autoimmune, allergic and inflammatory diseases, and in the prevention and/or treatment of diseases of the central nervous system (CNS), such as neurodegenerative diseases. The present invention further provides pharmaceutical compositions comprising the compounds of the instant invention and sale dosing regimens of these pharmaceutical compositions, which are easy to follow, and which result in a therapeutically effective amount of these compounds in vivo.
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Page/Page column 70
(2009/04/24)
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- Asymmetric Sommelet-Hauser rearrangement of N-benzylic ammonium salts
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(Chemical Equation Presented) [2,3] over [1,2]: The asymmetric Sommelet-Hauser rearrangement of an ammonium salt derived from N-benzylic proline-derived or N-benzylic glycine (-)-8-phenylmenthol ester is shown to proceed with remarkably high levels of stereoselectivity. The method provides unique and efficient access to optically active α-aryl amino acid derivatives.
- Tayama, Eiji,Kimura, Hiroshi
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p. 8869 - 8871
(2008/09/19)
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- Type b botulism toxin inhibitors
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The invention relates to novel compounds of genera formula (I), with inhibitory properties for the type B botulism toxin activity, the methods for preparation thereof and corresponding pharmaceutical compositions. The invention further relates to correspo
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- Protoberberines from Reissert-Compounds VIII [1]. Oxazoloisoquinolines, New and Efficient Educts for the Synthesis of 8-Oxoprotoberberines
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Certain benzylated oxazoloisoquinolinones readily available from Reissert compounds provided an efficient access to 8-oxoprotoberberines in three steps. A series of these new precursors as well as several oxoprotoberberines were prepared and the scope and limitation of this procedure were investigated.
- Reimann, Eberhard,Grasberger, Fritz,Polborn, Kurt
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p. 991 - 1014
(2007/10/03)
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- Parallel synthesis of glycomimetic libraries: targeting a C-type lectin.
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We have developed methods for the parallel synthesis of two libraries of non-carbohydrate-based analogues of mannose on a solid support. The natural product shikimic acid was used as a key building block. The ability of the compounds to block the binding of the C-type lectin MBP-A to a mannosylated surface was assessed in a high-throughput assay. Ten library members with inhibitory activities equivalent to that of alpha-methyl mannopyranoside were identified. [reaction: see text]
- Schuster, Michael C,Mann, David A,Buchholz, Tonia J,Johnson, Kathryn M,Thomas, William D,Kiessling, Laura L
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p. 1407 - 1410
(2007/10/03)
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- Matrix metalloproteinase inhibitors
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Compounds are provided that bind allosterically to the catalytic domain of MMP-13 and comprise a hydrophobic group, first and second hydrogen bond acceptors and at least one, and preferably both, of a third hydrogen bond acceptor and a second hydrophobic group. Cartesian coordinates for centroids of the above features are defined in the specification. When the ligand binds to MMP-13, the first, second and third (when present) hydrogen bond acceptors bond respectively with Thr245, Thr 247 and Met 253, the first hydrophobic group locates within the S1' channel of MMP-13 and the second hydrophobic group (when present) is relatively open to solvent. The compounds specifically inhibit the matrix metalloproteinase-13 enzyme and thus are useful for treating diseases resulting from tissue breakdown, such as heart disease, multiple sclerosis, arthritis, atherosclerosis, and osteoporosis.
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- Pseudopeptide compounds having an inhibiting activity with respect to paths activated by proteins with active tyrosine kinase activity and pharmaceutical compositions containing same
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The invention concerns a compound corresponding to general formula (1) wherein, in particular, R2 represents a phenylmethyl or naphthylmethyl or cyclohexylmethyl radical, 2- and 3-pryidinylmethyl, substituted on the cycle in meta or para positi
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- Alpha-and beta- substituted trifluoromethyl ketones as phospholipase inhibitors
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Inhibitors of the cytosolic phospholipase A2 enzymes are provided which are of use in controlling a wide variety of inflammatory diseases. The inhibitors of the present invention have the general formula where X, Z, R1, R2, R3, R4, Ra and Rb are as defined in the specification.
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- Alpha-and beta-substituted trifluoromethyl ketones as phospholipase inhibitors
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Inhibitors of the cytosolic phospholipase A2 enzymes are provided which are of use in controlling a wide variety of inflammatory diseases. The inhibitors of the present invention have the general formula where X, Z, R1, R2, R3, R4, Raand Rbare as defined in the specification.
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- Phosphonic acid derivatives as inhibitors of protein tyrosine phosphatase IB (PTP-IB)
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The invention encompasses the novel class of compounds represented by formula I which are inhibitors of the PTP-1B enzyme. The invention also encompasses pharmaceutical compositions and methods of treating or preventing PTP-1B mediated diseases, including diabetes, obesity, and diabetes-related diseases.
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- Protease inhibitors
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The present invention provides compounds of formula (I) which inhibit proteases, including cathepsin K, pharmaceutical compositions of such compounds, and methods for treating diseases of excessive bone loss or cartilage or matrix degradation, including osteoporosis; gingival disease including gingivitis and periodontitis; arthritis, more specifically, osteoarthritis and rheumatoid arthritis; Paget's disease; hypercalcemia or malignancy; and metabolic bone disease therewith.
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- Laser flash photolysis studies on the first superoxide thermal source. First direct measurements of the rates of solvent-assisted 1,2-hydrogen atom shifts and a proposed new mechanism for this unusual rearrangement
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The thermal decomposition of bis(4-carboxybenzyl)hyponitrite (SOTS-1) in aerated water under physiological conditions has previously been shown to give the superoxide radical anion in a yield of 40 mol % (Ingold, K. U.; et al. J. Am. Chem. Soc. 1997, 119, 12364). The absolute kinetics of the elementary reactions involved in the cascade of events leading from the first-formed water-soluble benzyloxyl radical to superoxide have been determined by laser flash photolysis. On the basis of these kinetics it is concluded that SOTS-1 will be suitable for studies of superoxide-induced oxidative stress in most biological systems. A water-assisted 1,2-H shift converting benzyloxyl into the benzyl ketyl radical is an important step in the above reaction cascade. The kinetics of the 1,2-H shift assisted by H2O, D2O, and a number of nucleophilic alcohols have been measured for the first time. These data have led to a proposed new mechanism involving the initial formation of a ketyl radical anion and an oxonium cation which generally collapse to give the neutral ketyl radical as the first observable product on the time scale of our experiments (ca. 80 ns).
- Konya, Klara G.,Paul, Thomas,Lin, Shuqiong,Lusztyk, Janusz,Ingold
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p. 7518 - 7527
(2007/10/03)
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- Small peptides containing phosphotyrosine and adjacent αMe- phosphotyrosine or its mimetics as highly potent inhibitors of Grb2 SH2 domain
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A series of small peptides with the sequence mAZ-pTyr-Xaa-Asn-NH2, where Xaa denotes α-methylphosphotyrosine or its carboxylic mimetics, were synthesized as inhibitors of the Grb2 SH2 domain. Peptide 3 with (α-Me)pTyr as Xaa has the highest aff
- Liu, Wang-Qing,Vidal, Michel,Gresh, Nohad,Roques, Bernard P.,Garbay, Christiane
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p. 3737 - 3741
(2007/10/03)
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- Stereospecific synthesis of 4-carboxyphenylalanine and derivatives for use in Fmoc-based solid-phase peptide synthesis
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Starting from N(α)-benzyloxycarbonyl-L-tyrosine(O-triflate) benzyl ester, we have prepared enantiomerically pure 4-carboxyphenylalanine and 4-methoxycarbonylphenylalanine derivatives using palladium (0) catalyzed carbonylation reactions. These unnatural amino acids were suitably protected and were used in solid-phase peptide synthesis using the Fmoc/t-butyl approach.
- Wang, Wei,Obeyesekere, Nihal U.,McMurray, John S.
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p. 6661 - 6664
(2007/10/03)
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- Analogs of tyrosine sulfate or tyrosine phosphate containing peptides
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Analogs of Tyrosine Sulfate or Tyrosine Phosphate containing peptides, the novel intermediate compounds used in the preparation of these analogs, as well as a method for suppressing appetite in subjects by administering to the subject an effective amount
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- Process for introducing fluorine into biologically active materials
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Radioactive fluorine can be easily introduced into biologically active molecules containing amino groups. A p-bromomethyl benzoyl group is coupled to the amino group of the biologically active molecule, and bromine is displaced by fluorine. Alternatively,
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- Carboxylic Acids and Tetrazoles as Isosteric Replacements for Sulfate in Cholecystokinin Analogues
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A series of analogues of the satiely-inducing peptide cholecystokinin (CCK-8) was prepared in which the sulfated tyrosine required for activation of peripheral receptors was replaced with a carboxy(alkyl)- or tetrazolyl(alkyl)-phenylalanine to investigate whether an organic acid could serve the role of the sulfate group at the receptor.The necessary intermediates were prepared by previously reported procedures or by alkylation of carboxy(alkyl)- or tetrazolyl(alkyl)phenylmethyl bromides with a glycine-derived anion followed by protecting-group manipulations, and these were incorporated into derivatives of acetyl-CCK-7 using solid-phase synthesis.Peptide analogues were evaluated in a CCK-binding assay for affinity for either peripheral (CCK-B) receptors using homogenated rat pancreatic membranes as the receptor source or for central (CCK-B) receptors using bovine striatum as the receptor source.They were further evaluated for effects on food intake in rats after intraperitoneal (ip) injection.A number of the compounds reported are active in the CCK-A receptor binding assay although less potent than acetyl-CCK-7 and decrease food intake with comparable potency to acetyl-CCK-7.In a meal feeding model designed to assess appetite suppressant activity, acetyl-CCK-7 has an ED50 of 7 nmol/kg ip, while the ED50s of Ac-Phe(4-CH2CO2H)-Met-Gly-Trp-Met-Asp-Phe-NH2 (28) and Ac-Phe-Met-Gly-Trp-Met-Asp-Phe-NH2 (34) were 9 and 11 nmol/kg ip, respectively.An analogue of 28 lacking the N-terminal acetamido group, 3-propanoyl-Met-Gly-Trp-Met-Asp-Phe-NH2 (50), was also active in the meal feeding assay with an ED50 of 3 nmol/kg ip.Its anorexic effect was blocked by simultaneous administration of the CCK-A receptor antagonist MK 329, indicating that the observed anorexic activity is mediated by CCK-A receptors.We conclude from this work that the requirement for a negative charge at the CCK-A receptor provided in the natural substrate by a sulfate group can be satisfied by organic acids.
- Tilley, Jefferson W.,Danho, Waleed,Lovey, Kathleen,Wagner, Rolf,Swistok, Joseph,et al.
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p. 1125 - 1136
(2007/10/02)
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- (6R,6S)-5,8,10-Trideaza-5,6,7,8-tetrahydrofolate and (6R,6S)-5,8,10-Trideaza-5,6,7,8-tetrahydropteroyl-L-ornithine as Potential Antifolates and Antitumor Agents
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(6R,6S)-5,8,10-Trideaza-5,6,7,8-tetrahydropteroic acid was synthesized in several steps from 4,4-(ethylenedioxy)cyclohexanone and triphenylphosphonium bromide and was elaborated to (6R,6S)-5,8,10-trideaza-5,6,7,8-tetrahydr
- Rosowsky, Andre,Forsch, Ronald A.,Moran, Richard G.
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p. 709 - 715
(2007/10/02)
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- Pyrazole oxime derivatives and compositions
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A pyrazole oxime derivative represented by the general formula (I) which is useful as an insecticide and fungicide, STR1 wherein the structural elements are defined in the specification, and the method of controlling said pests. The compounds represented by the general formula (I) can be synthesized by the methods disclosed in the specification.
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- A PROSTHETIC GROUP FOR THE RAPID INTRODUCTION OF FLUORINE INTO PEPTIDES AND FUNCTIONALIZED DRUGS
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Fluoride ion as the tetrabutylammonium salt displaces bromide in para-substituted benzyl bromides in acetonitrile or dimethylformamide.The p-bromomethyl benzoyl (BMB) group has been coupled to amino groups, including peptide amino groups, via its N-hydrox
- Jacobson, Kenneth A.,Furlano, David C.,Kirk, Kenneth L.
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p. 339 - 348
(2007/10/02)
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