- Macrocyclic squaramides as ion pair receptors and fluorescent sensors selective towards sulfates
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Through the high dilution technique, we obtained macrocyclic ion pair receptorsR1andR2, an anion receptorR3, and a fluorescent sensorR4using a combination of particular members of simple libraries consisting of synthesized diamines and methyl squarates, r
- Zaleskaya, Marta,Jagleniec, Damian,Romański, Jan
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Read Online
- Atropisomerism in azadipeptides: evaluation of N1-methylation and thioamide introduction
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Abstract Cbz-protected azadipeptides, designed as structurally reduced model compounds, were synthesized and investigated with respect to the occurrence of atropisomerism. Methylation at the carbamate nitrogen caused mixtures of E and Z isomers in Cbz-sar
- Ottersbach, Philipp A.,Schnakenburg, Gregor,Gütschow, Michael
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Read Online
- Multikilogram Synthesis of a Potent Dual Bcl-2/Bcl-xL Antagonist. 1. Manufacture of the Acid Moiety and Development of Some Key Reactions
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Our efforts toward the process development of drug candidate 1 are described in a series of two papers. This manuscript focuses on the synthesis of kilogram quantities of acid precursor 2 to provide batches of material for preclinical studies and first-in
- Hardouin, Christophe,Baillard, Sandrine,Barière, Fran?ois,Copin, Chloé,Craquelin, Anthony,Janvier, Solenn,Lemaitre, Sylvain,Le Roux, Stéphane,Russo, Olivier,Samson, Sébastien
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p. 652 - 669
(2019/12/24)
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- Identification of Small-Molecule Modulators of Diguanylate Cyclase by FRET-Based High-Throughput Screening
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The bacterial second messenger cyclic diguanosine monophosphate (c-di-GMP) is a key regulator of cellular motility, the cell cycle, and biofilm formation with its resultant antibiotic tolerance, which can make chronic infections difficult to treat. Therefore, diguanylate cyclases, which regulate the spatiotemporal production of c-di-GMP, might be attractive drug targets for control of biofilm formation that is part of chronic infections. We present a FRET-based biochemical high-throughput screening approach coupled with detailed structure–activity studies to identify synthetic small-molecule modulators of the diguanylate cyclase DgcA from Caulobacter crescentus. We identified a set of seven small molecules that regulate DgcA enzymatic activity in the low-micromolar range. Subsequent structure–activity studies on selected scaffolds revealed a remarkable diversity of modulatory behavior, including slight chemical substitutions that reverse the effects from allosteric enzyme inhibition to activation. The compounds identified represent new chemotypes and are potentially developable into chemical genetic tools for the dissection of c-di-GMP signaling networks and alteration of c-di-GMP-associated phenotypes. In sum, our studies underline the importance of detailed mechanism-of-action studies for inhibitors of c-di-GMP signaling and demonstrate the complex interplay between synthetic small molecules and the regulatory mechanisms that control the activity of diguanylate cyclases.
- Christen, Matthias,Kamischke, Cassandra,Kulasekara, Hemantha D.,Olivas, Kathleen C.,Kulasekara, Bridget R.,Christen, Beat,Kline, Toni,Miller, Samuel I.
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p. 394 - 407
(2019/01/04)
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- Hybrids of arenobufagin and benzoisoselenazol reducing the cardiotoxicity of arenobufagin
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Arenobufagin is a naturally occurring bufadienolide showing promising antitumor activity accompanied however with apparent cardiac toxicity. Following the recent discovery that oxidative damage possibly be an important cause of the cardiac toxicity of cardenolides, a strategy fusing the antitumor agent arenobufagin with a benzoisoselenazol fragment, a reactive oxygen species (ROS) scavenger, has been developed. Six novel hybrids were synthesized and their ROS scavenging activities as well as their in vitro cytotoxicity against the human hepatocellular carcinoma cell line HepG2, an adriamycin-resistant subline HepG2/ADM, and the human myocardial cell line AC16 were evaluated. The results indicate that the hybrids exhibit various degrees of in vitro ROS scavenging activities, and weaker cytotoxicity than that of arenobufagin against the myocardial cell line AC16. These findings suggest the feasibility of a strategy in which the cardiotoxicity of the potential antitumor agent arenobufagin is reduced.
- Hou, Wen,Huang, Zhi-Xing,Xu, Hong-Gui,Lin, Jing,Zhang, Dong-Mei,Peng, Qun-Long,Lin, Hui,Chang, Yi-Qun,Wang, Long-Hai,Yao, Zhe,Sun, Ping-Hua,Chen, Wei-Min
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p. 3391 - 3394
(2018/09/11)
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- The synthesis of Nα-protected amino hydroxamic acids from Nα-protected amino acids employing versatile chlorinating agent CPI-Cl
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Racemization free synthesis of Nα-protected amino hydroxamic acids from Nα-protected amino acids employing the versatile chlorinating reagent CPI-Cl has been described in one-pot. The present protocol has shown compability towards urethane protecting groups like Boc, Cbz and Fmoc, and side chain protections of amino acids showed complete tolerance.
- Vathsala,Srinivasulu,Santhosh,Sureshbabu, Vommina V.
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p. 449 - 457
(2019/03/08)
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- THERAPEUTIC COMPOUNDS AND FORMULATIONS FOR INTRANASAL DELIVERY
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Certain embodiments of the invention provide a formulation suitable for nasal administration comprising water, a prodrug of a therapeutic agent, and an enzyme that is suitable for intranasal conversion of the prodrug to the therapeutic agent, as well as methods of use thereof.
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Page/Page column 28-29
(2016/10/24)
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- PERIPHERALLY RESTRICTED GABA POSITIVE ALLOSTERIC MODULATORS FOR THE TREATMENT OF IRRITABLE BOWEL SYNDROME AND OTHER AILMENTS OF THE PERIPHERAL NERVOUS SYSTEM
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The present invention provides compounds and compositions which are positive allosteric modulators of GABA-A receptors that selectively target the peripheral nervous system and organs of the body, and which do not pass through the blood-brain barrier. The compounds and compositions of the present invention are useful for treatment of diseases or disorders which are mediated by GABA-A neuronal activity, such as, for example, visceral pain, gut motility, irritable bowel syndrome, functional abdominal pain, functional idiopathic diarrhea, inflammatory bowel diseases, drug induced pain, bile salt malabsorption, lactase or other carbohydrate intolerance.
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Paragraph 0120-0121
(2016/01/12)
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- Pyrrolopyrimidine-inhibitors with hydantoin moiety as spacer can explore P4/S4 interaction on plasmin
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In the development of plasmin inhibitors, a novel chemotype, pyrrolopyrimidine scaffold possessing two motifs, a hydantoin-containing P4 moiety and a warhead-containing P1 moiety, is uncovered. A unique feature of the new line of the plasmin inhibitors is
- Teno, Naoki,Gohda, Keigo,Wanaka, Keiko,Tsuda, Yuko,Sueda, Takuya,Yamashita, Yukiko,Otsubo, Tadamune
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supporting information
p. 2339 - 2352
(2014/04/17)
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- Structural optimization of azadipeptide nitriles strongly increases association rates and allows the development of selective cathepsin inhibitors
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Using the example of cathepsin K, we demonstrate the design of highly potent and selective azadipeptide nitrile inhibitors. A systematic scan with respect to P2 and P3 substituents was carried out. Structural modifications strongly affected the enzyme-inh
- Frizler, Maxim,Lohr, Friederike,Furtmann, Norbert,Kl?s, Julia,Gütschow, Michael
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supporting information; experimental part
p. 396 - 400
(2011/03/18)
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- FURAZANOBENZIMIDAZOLES AS PRODRUGS TO TREAT NEOPLASTIC OR AUTOIMMUNE DISEASES
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A compound of formula (II) wherein (a) represents a divalent benzene residue which is unsubstituted or substituted by one or two additional substituents independently selected from lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, phenyl, hydroxy, lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, phenyl-lower alkoxy, lower alkylcarbonyloxy, amino, mono(lower alkyl)amino, di(lower alkyl)amino, mono(lower alkenyl)amino, di(lower alkenyl)amino, lower alkoxycarbonylamino, lower alkylcarbonylamino, substituted amino wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl, lower alkylcarbonyl, carboxy, lower 15 alkoxycarbonyl, cyano, halogen, and nitro; or wherein two adjacent substituents can be methylenedioxy; or a divalent pyridine residue (Z = N) which is unsubstituted or substituted additionally by lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy,amino, optionally substituted by one or two substituents selected from lower alkyl, lower alkenyl and alkylcarbonyl, halo-20 lower alkyl, lower alkoxy-lower alkyl, or halogen; R1 represents hydrogen, lower alkylcarbonyl, hydroxy-lower alkylor cyano-loweralkyl; and R2 represents a group selected from: (b), (c) and (d); or pharmaceutically acceptable salts thereof.
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Page/Page column 45; 46
(2011/02/24)
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- Discovery of potent, selective, and orally bioavailable quinoline-based dipeptidyl peptidase IV inhibitors targeting Lys554
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Dipeptidyl peptidase IV (DPP-4) inhibition is a validated therapeutic option for type 2 diabetes, exhibiting multiple antidiabetic effects with little or no risk of hypoglycemia. In our studies involving non-covalent DPP-4 inhibitors, a novel series of quinoline-based inhibitors were designed based on the co-crystal structure of isoquinolone 2 in complex with DPP-4 to target the side chain of Lys554. Synthesis and evaluation of designed compounds revealed 1-[3-(aminomethyl)-4-(4-methylphenyl)-2-(2-methylpropyl)quinolin-6-yl] piperazine-2,5-dione (1) as a potent, selective, and orally active DPP-4 inhibitor (IC50 = 1.3 nM) with long-lasting ex vivo activity in dogs and excellent antihyperglycemic effects in rats. A docking study of compound 1 revealed a hydrogen-bonding interaction with the side chain of Lys554, suggesting this residue as a potential target site useful for enhancing DPP-4 inhibition.
- Maezaki, Hironobu,Banno, Yoshihiro,Miyamoto, Yasufumi,Moritou, Yuusuke,Asakawa, Tomoko,Kataoka, Osamu,Takeuchi, Koji,Suzuki, Nobuhiro,Ikedo, Koji,Kosaka, Takuo,Sasaki, Masako,Tsubotani, Shigetoshi,Tani, Akiyoshi,Funami, Miyuki,Yamamoto, Yoshio,Tawada, Michiko,Aertgeerts, Kathleen,Yano, Jason,Oi, Satoru
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experimental part
p. 4482 - 4498
(2011/09/19)
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- AMINO TRICYCLIC-NUCLEOSIDE COMPOUNDS, COMPOSITIONS, AND METHODS OF USE
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Provided are compounds of Formula (I) or a pharmaceutically acceptable salt or solvate thereof. The compounds and compositions are useful for treating viral infections caused by the Flaviviridae family of viruses.
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Page/Page column 27
(2009/04/24)
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- The synthesis, structure and reactivity of 1-thioxotetrahydropyridazino[1,2-α][1,2,4]triazin-4(1H)-one
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The synthesis of 1-thioxotetrahydropyridazino[1,2-a][1,2,4]triazin-4-(1H)-one 3 in five steps from tert-butyl carbazate and its transformation into 3-benzylidene and 1-amino derivatives are described. Its crystal structure is presented showing it to be an
- Jarrett, Sandra,Brown, Ainka,Singh-Wilmot, Marvadeen
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experimental part
p. 2755 - 2768
(2010/04/25)
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- Tricyclic compounds, a process for their preparation and pharmaceutical compositions containing them
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Compounds of formula (I): wherein A represents a 5, 6 or 7-membered (hetero)aromatic or non-aromatic ring,n and n′ represent 0, 1 or 2X represents an alkylene chain as defined in the description,R3 represents an aryl or heteroaryl group,one of the groups R1 and R2 represents a hydrogen atom and the other represents a group of formula (II) as defined in the description. Medicinal products containing the same which are useful in treating conditions involving a defect in apoptosis.
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Page/Page column 10
(2008/12/07)
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- Ethyl-4,4,4-trifluoroacetoacetate (ETFAA), a powerful building block for enantiopure chirons in trifluoromethyl-β-amino acid series
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Herein are studied new transformations of ethyl-4,4,4-trifluoroacetoacetate (ETFAA), giving access to a series of enantiopure chirons bearing both a trifluoromethyl group and an amino moiety. The key intermediate is obtained optically pure by a resolution
- Michaut, Valérie,Metz, Fran?ois,Paris, Jean-Marc,Plaquevent, Jean-Christophe
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p. 889 - 895
(2008/03/14)
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- Synthesis and evaluation of ketophosph(on)ates as β-lactamase inhibitors
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A series of amidoketophosph(on)ates of general structure PhCH 2OCONHCH(R)COCHR′(CH2)n(O)P-(O 2-)(O)R″ (R = H, CH3; R′ = H, CH3; n = 0, 1; R″ = H, CH3, Et, Ph) have bee
- Perumal, Senthil K.,Pratt
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p. 4778 - 4785
(2007/10/03)
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- Synthesis and metal complexation properties of Ph-DTPA and Ph-TTHA: Novel radionuclide chelating agents for use in nuclear medicine
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We wish to report the synthesis and metal complexation properties of new radionuclide chelating agents for use in nuclear medicine. The strategy includes the facile preparation of rigid analogues of DTPA and TTHA possessing an aromatic ring. The aromatic
- Gouin, Sebastien G.,Gestin, Jean-Francois,Monrandeau, Laurence,Segat-Dioury, Fabienne,Meslin, Jean Claude,Deniaud, David
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p. 454 - 461
(2007/10/03)
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- Asparagine deaminase catalytic antibodies
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Transition state analogs are described which may be used to elicit antibodies that catalyze the conversion of asparagine to aspartic acid. Synthetic schemes are disclosed for making the transition state analogs which can than be attached to a carrier molecule to form an immunoconjugate. Immunoconjugates can be administered to an animal for the purpose of raising antibodies. Antibodies can in turn be used in pharmaceutical compositions which can be given to patients as part of a method of treating various conditions, particularly cancer.
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Page/Page column 11
(2010/02/11)
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- FUSED HETEROCYCLIC COMPOUNDS
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A compound represented by the formula wherein ring A is an optionally substituted 5- to 10-membered aromatic ring; R1 and R2 are the same or different and each is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X and Y are the same or different and each is a bond, -O-, -S-, -SO-, -SO?2#191- or -NR3- (R3 is a hydrogen atom or an optionally substituted hydrocarbon group); and L is a divalent hydrocarbon group, or a salt thereof shows a superior peptidase-inhibitory activity and is useful as a prophylactic or therapeutic agent of diabetes and the like.
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- Alternative Method for the Resolution of 1-Benzoyl-2-tert-butyl-3-methyl-1,3-imidazolidin-4-one
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The title heterocycles, which are useful chiral precursors for the asymmetric synthesis of α-amino acids, an be prepared in enantiomerically pure form via the separation of diastereomeric derivatives incorporating (S)-α-methyl-benzylamine.
- Juaristi, Eusebio,Rizo, Benito,Natal, Vicente,Escalante, Jaime,Regla, Ignacio
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p. 821 - 826
(2007/10/02)
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- Amino acid amides of 2-benzimidazole as acid-stable prodrugs of potential inhibitors of H+/K+ ATPase
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A series of amino acid amides of 2-benzimidazole were prepared and found to possess gastric antisecretory activity on oral administration. (Glycylaminobenzyl)sulfinyl compound 23a, stable in artificial gastric juice (pH 1.2), was given orally to dogs.It was absorbed efficiently and converted into aniline derivative 7a which showed a very high plasma concentration.Compound 23a was hydrolyzed by the action of aminopeptidase present in plasma or the brush border fraction of the small intestine to release the terminal glycine. o-Aniline derivatives showed good activity in in vitro H+/K+-ATPase inhibition as well as in the inhibition of histamine stimulated acid secretion in isolated bullfrog gastric mucosa.Although these o-aniline derivatives showed no or weak gastric antisecretory activity in rat by id administration, they were active when administered ip.Therefore, these amino acid amides were considered to be acid stable prodrugs of proton pump inhibiting o-aniline derivatives.The mechanism of H+/K+-ATPase inhibition of 7a was also examined.
- Hirai, K,Koike, H,Ishiba, T,Ueda, S,Makino, I,et al.
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p. 143 - 158
(2007/10/02)
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- Hydrolysis of an Amide in a Carboxypeptidase Model Using Co(III) and Bifunctional Catalysts
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The ability of a metal ion to cooperate with various inter- and intramolecular acids and bases and promote amide hydrolysis has been investigated.Phenolic and carboxylic functional groups were placed within reach of Co(III)-chelated amides in complexes th
- Schepartz, Alanna,Breslow, Ronald
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p. 1814 - 1826
(2007/10/02)
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- Synthesis and biological activity of (3,5-disubstituted-1H-1,2,4-triazol-1-yl)benzophenone derivatives (1)
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The synthesis of (5-acylaminomethyl-3-carbamoyl-1H-1,2,4-triazol-1-yl)benzophenone derivatives is described. Acylation of the key intermediate, 1-benzoylphenylazo-1-aminoacetamide followed by cyclization in the presence of acid afforded 1H-1,2,4-triazole derivates. These compounds were evaluated for their central nervous system (CNS) activity. Some of these compounds exhibited high activities in anti-pentylene tetrazole and rotarod test in mice orally administered.
- Hirai,Sugimoto,Ishiba,et al.
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p. 1363 - 1369
(2007/10/02)
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- New Synthesis of Diazepam and the Related 1,4-Benzodiazepines by means of Palladium-Catalyzed Carbonylation
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A new synthesis of diazepam (5) was achieved by application of palladium-catalyzed carbonylation to the compound 3 prepared from o-bromoaniline derivative 1 and the amino acid 2, and this procedure was also used for the synthesis of poisonous metabolites
- Ishikura, Minoru,Mori, Miwako,Ikeda, Toshihito,Terashima, Masanao,Ban, Yoshio
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p. 2456 - 2461
(2007/10/02)
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- Amino acid amide derivatives of 2-[3-(aminomethyl)-4H-1,2,4-triazol-4-yl]benzophenones, a novel class of annelated peptidoaminobenzophenones
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A series of the title compounds was prepared via condensation of the 3-(aminomethyl)triazolylbenzophenone with N-protected amino acids, followed by deprotection, amination of the 3-[(chloroacetamido)methyl]triazolylbenzophenone, or reduction of the relevant azide derivative. Some of the title compounds were also derived directly from the quinazolines by acid-induced rearrangement, followed by deprotection. These new amino acid amide derivatives of the triazolylbenzophenones were evaluated for central nervous system (CNS) activity. Members of this class of compounds exhibited a high level of CNS activities. For example, 2',5-dichloro-2-[3-[(glycylamino)methyl]-5-methyl-4H-1,2,4-triazol-4-yl ]benzophenone was as active as triazolam, with an ED50 of 0.58 mg/kg (mice, po), against antifighting activity in the foot shock-induced fighting test. Other triazolylbenzophenone derivatives showed similar pharmacological activities.
- Hirai,Fujishita,Ishiba,Sugimoto,Matsutani,Tsukinoki,Hirose
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p. 1466 - 1473
(2007/10/02)
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- NEW SYNTHESIS OF DIAZEPINONE SKELETON USING PALLADIUM CATALYZED CARBONYLATION
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Palladium catalyzed carbonylation to the secondary amine(10) which was easily prepared from N-methyl-2-bromo-4-chloroaniline (1a) and carbobenzyloxyglycine(2a) gave 3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione derivative(11) in the yield of 30percent.N-Ace
- Mori, Miwako,Ishikura, Minoru,Ikeda, Toshihito,Ban, Yoshio
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p. 1491 - 1494
(2007/10/02)
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- Novel Peptidoaminobenzophenones, Terminal N-Substituted Peptidoaminobenzophenones, and N-(Acylglycyl)aminobenzophenones as Open-Ring Derivatives of Benzodiazepines
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Peptidoaminobenzophenones (1), terminal N-substituted peptidoaminobenzophenones (14), and acylglycylaminobenzophenones (16) were prepared as a novel series of ring-opened derivatives of 1,4-benzodiazepine.Z-Gly- and Z-Ala-N-methylaminobenzophenones (4) we
- Hirai, Kentaro,Ishiba, Teruyuki,Sugimoto, Hirohiko,Fujishita, Toshio,Tsukinoki, Yuji,Hirose, Katsumi
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- Lipophilic and hydrophilic esters of 4-acetyl-2-(2-hydroxyethyl)-5,6-bis (4-chlorophenyl)2h-pyridazin-3-one as antihypertensive agents
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In an attempt to enhance the antihypertensive activity of 4-acetyl-2-(2-hydroxyethyl)-5,6-bis(4-chlorophenyl)-2H-pyridazin-3-one, (1), a series of lipophilic and hydrophilic esters was synthesized. These derivatives possessed increased lipid and aqueous s
- Fogt,Scozzie,Heilman,Powers
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p. 1445 - 1448
(2007/10/02)
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