- BIAMINOQUINOLINES AND NANOFORMULATIONS FOR CANCER TREATMENT
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The present invention provides bisaminoquinoline compounds of Formula (I). The present invention also provides nanocarriers comprising compounds of the present invention, and methods of using the nanocarriers for treating diseases and imaging.
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Paragraph 0162
(2021/04/01)
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- 6-MEMBERED CYCLIC AMINES OR LACTAMES SUBSTITUTED WITH UREA AND PHENYL
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The present invention relates to a compound according to general formula (I) which acts as a modulator of FPR2 and can be used in the treatment and/or prophylaxis of disorders which are at least partially mediated by FPR2.
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Paragraph 0394; 0396
(2018/04/13)
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- Discovery of Tetrahydroisoquinoline-Containing CXCR4 Antagonists with Improved in Vitro ADMET Properties
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CXCR4 is a seven-transmembrane receptor expressed by hematopoietic stem cells and progeny, as well as by ≥48 different cancers types. CXCL12, the only chemokine ligand of CXCR4, is secreted within the tumor microenvironment, providing sanctuary for CXCR4+ tumor cells from immune surveillance and chemotherapeutic elimination by (1) stimulating prosurvival signaling and (2) recruiting CXCR4+ immunosuppressive leukocytes. Additionally, distant CXCL12-rich niches attract and support CXCR4+ metastatic growths. Accordingly, CXCR4 antagonists can potentially obstruct CXCR4-mediated prosurvival signaling, recondition the CXCR4+ leukocyte infiltrate from immunosuppressive to immunoreactive, and inhibit CXCR4+ cancer cell metastasis. Current small molecule CXCR4 antagonists suffer from poor oral bioavailability and off-target liabilities. Herein, we report a series of novel tetrahydroisoquinoline-containing CXCR4 antagonists designed to improve intestinal absorption and off-target profiles. Structure-activity relationships regarding CXCR4 potency, intestinal permeability, metabolic stability, and cytochrome P450 inhibition are presented.
- Miller, Eric J.,Jecs, Edgars,Truax, Valarie M.,Katzman, Brooke M.,Tahirovic, Yesim A.,Wilson, Robert J.,Kuo, Katie M.,Kim, Michelle B.,Nguyen, Huy H.,Saindane, Manohar T.,Zhao, Huanyu,Wang, Tao,Sum, Chi S.,Cvijic, Mary E.,Schroeder, Gretchen M.,Wilson, Lawrence J.,Liotta, Dennis C.
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supporting information
p. 946 - 979
(2018/02/17)
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- PROTEASE INHIBITORS HAVING ENHANCED FEATURES
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Provided herein (among other things) are protease inhibitor compounds having enhanced features, along with methods for administering such compounds. For example, the subject compounds can be administered without concomitant administration of a CYP3A4 inhibitor, have increased therapeutic index and/or increased potency, and are low-resistance inducing in nature.
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Paragraph 0158
(2017/02/28)
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- Compounds and methods for protease detection
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Alternative methods for the detection and measurement of proteases in biological samples and compounds which allow for such detection are required to allow for rapid and selective identification of these enzymes. Compounds which allow for selective identification of these enzymes are provided with assays and kits for their use.
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Page/Page column 15; 16
(2016/06/06)
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- From in vitro to in cellulo: Structure-activity relationship of (2-nitrophenyl)methanol derivatives as inhibitors of PqsD in Pseudomonas aeruginosa
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Recent studies have shown that compounds based on a (2-nitrophenyl)methanol scaffold are promising inhibitors of PqsD, a key enzyme of signal molecule biosynthesis in the cell-to-cell communication of Pseudomonas aeruginosa. The most promising molecule displayed anti-biofilm activity and a tight-binding mode of action. Herein, we report on the convenient synthesis and biochemical evaluation of a comprehensive series of (2-nitrophenyl)methanol derivatives. The in vitro potency of these inhibitors against recombinant PqsD as well as the effect of selected compounds on the production of the signal molecules HHQ and PQS in P. aeruginosa were examined. The gathered data allowed the establishment of a structure-activity relationship, which was used to design fluorescent inhibitors, and finally, led to the discovery of (2-nitrophenyl)methanol derivatives with improved in cellulo efficacy providing new perspectives towards the application of PqsD inhibitors as anti-infectives. This journal is the Partner Organisations 2014.
- Storz, Michael P.,Allegretta, Giuseppe,Kirsch, Benjamin,Empting, Martin,Hartmann, Rolf W.
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supporting information
p. 6094 - 6104
(2014/08/05)
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- Discovery of tetrahydroisoquinoline-based CXCR4 antagonists
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A de novo hit-to-lead effort involving the redesign of benzimidazole- containing antagonists of the CXCR4 receptor resulted in the discovery of a novel series of 1,2,3,4-tetrahydroisoquinoline (TIQ) analogues. In general, this series of compounds show good potencies (3-650 nM) in assays involving CXCR4 function, including both inhibition of attachment of X4 HIV-1IIIB virus in MAGI-CCR5/CXCR4 cells and inhibition of calcium release in Chem-1 cells. Series profiling permitted the identification of TIQ-(R)-stereoisomer 15 as a potent and selective CXCR4 antagonist lead candidate with a promising in vitro profile. The drug-like properties of 15 were determined in ADME in vitro studies, revealing low metabolic liability potential. Further in vivo evaluations included pharmacokinetic experiments in rats and mice, where 15 was shown to have oral bioavailability (F = 63%) and resulted in the mobilization of white blood cells (WBCs) in a dose-dependent manner.
- Truax, Valarie M.,Zhao, Huanyu,Katzman, Brooke M.,Prosser, Anthony R.,Alcaraz, Ana A.,Saindane, Manohar T.,Howard, Randy B.,Culver, Deborah,Arrendale, Richard F.,Gruddanti, Prahbakar R.,Evers, Taylor J.,Natchus, Michael G.,Snyder, James P.,Liotta, Dennis C.,Wilson, Lawrence J.
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supporting information
p. 1025 - 1030
(2013/12/04)
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- AZABENZIMIDAZOLES AS RESPIRATORY SYNCYTIAL VIRUS ANTIVIRAL AGENTS
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A compound satisfying formula I, a prodrug, N-oxide, addition salt, quaternary metal complex, or a stereochemically isomeric form thereof; (formula I) compositions contain these compounds as active ingredient and processes for preparing these compounds and compositions.
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Page/Page column 70
(2012/06/30)
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- Validation of PqsD as an anti-biofilm target in pseudomonas aeruginosa by development of small-molecule inhibitors
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2-Heptyl-4-hydroxyquinoline (HHQ) and Pseudomonas quinolone signal (PQS) are involved in the regulation of virulence factor production and biofilm formation in Pseudomonas aeruginosa. PqsD is a key enzyme in the biosynthesis of these signal molecules. Using a ligand-based approach, we have identified the first class of PqsD inhibitors. Simplification and rigidization led to fragments with high ligand efficiencies. These small molecules repress HHQ and PQS production and biofilm formation in P. aeruginosa. This validates PqsD as a target for the development of anti-infectives.
- Storz, Michael P.,Maurer, Christine K.,Zimmer, Christina,Wagner, Nathalie,Brengel, Christian,De Jong, Johannes C.,Lucas, Simon,Muesken, Mathias,Haeussler, Susanne,Steinbach, Anke,Hartmann, Rolf W.
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supporting information
p. 16143 - 16146
(2012/11/07)
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- ACYCLIC 1,4-DIAMINES AND USES THEREOF
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This invention relates to novel compounds useful in the treatment of diseases associated with TRPV4 channel receptor. More specifically, this invention relates to certain acyclic diamines, which are agonists of TRPV4 channel receptors.
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Page/Page column 49; 145
(2008/06/13)
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- TETRAHYDROCARBOLINE COMPOUNDS AS ANTICANCER AGENTS
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Tetrahydrocarboline compounds, pharmaceutically acceptable salts, and prodrugs thereof; compositions that include a pharmaceutically acceptable carrier and one or more of the tetrahydrocarboline compounds, either alone or in combination with at least one
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Page/Page column 36
(2008/06/13)
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- N-methyl-5-tert-butyltryptamine: A novel, highly potent 5-HT(1D) receptor agonist
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It has been observed that reported 5-HT(1D) receptor agonists have at least one heteroatom (N, O, or S) on the 5-substituent of the indole. This has led to the hypothesis that a 5-substituent capable of participating in hydrogen bonding is critical for conveying high affinity. This article describes the synthesis and biological evaluation of a new series of 5- alkyltryptamine analogues, which does not have a heteroatom in the 5- substituent group. In contrast to the hypothesis, 5-alkyltryptamines all exhibit high binding affinities for the human 5-HT(1D) receptor. The size of the lipophilic alkyl group at the 5-position of the indole has significant impact on the 5-HT(1D) binding affinity. Compounds with a tert-butyl group at the 5-position such as 9d, 10, and 11 were identified. These analogues display high binding affinity (K(i) 1 nM) and moderate receptor selectivity in comparison with known antimigraine agents such as sumatriptan, naratriptan, rizatriptan, and VML-251.
- Xu, Yao-Chang,Schaus, John M.,Walker, Clint,Krushinski, Joe,Adham, Nika,Zgombick, John M.,Liang, Sidney X.,Kohlman, Dan T.,Audia, James E.
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p. 526 - 531
(2007/10/03)
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- Synthesis, CoMFA analysis, and receptor docking of 3,5-diacyl-2,4- dialkylpyridine derivatives as selective A3 adenosine receptor antagonists
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3,5-Diacyl-2,4-dialkyl-6-phenylpyridine derivatives have been found to be selective antagonists at both human and rat A3 adenosine receptors (Li et al. J. Med. Chem. 1998, 41, 3186-3201). In the present study, ring- constrained, fluoro, hydroxy, and other derivatives in this series have been synthesized and tested for affinity at adenosine receptors in radioligand binding assays. K(i) values at recombinant human and rat A3 adenosine receptors were determined using [125I]AB-MECA (N6-(4-amino-3-iodobenzyl)- 5'-N-methylcarbamoyladenosine). Selectivity for A3 adenosine receptors was determined vs radioligand binding at rat brain A1 and A(2A) receptors, and structure-activity relationships at various positions of the pyridine ring (the 3- and 5-acyl substituents and the 2- and 4-alkyl substituents) were probed. At the 5-position inclusion of a β-fluoroethyl (7) or a γ- fluoropropyl ester (26) was favorable for human A3 receptor affinity, resulting in K(i) values of 4.2 and 9.7 nM, respectively, while the pentafluoropropyl analogue was clearly less potent at human A3 receptors. At the 2-, 3-, and 4-positions, fluoro or hydroxy substitution failed to enhance potency and selectivity at human A3 receptors. Several analogues were nearly equipotent at rat and human A3 receptors. To further define the pharmacophore conformationally, a lactam, a lactone, and thiolactones were tested in adenosine receptor binding. The most potent analogue in this group was compound 34, in which a thiolactone was formed between 3- and 4-positions and which had a K(i) value of 248 nM at human A3 receptors. Using affinity data and a general pharmacophore model for A3 adenosine receptor antagonists recently proposed, we applied comparative molecular field analysis (CoMFA) to obtain a three dimensional quantitative structure-activity relationship for pyridine derivatives, having good predictability (r2(pred) = 0.873) for compounds in the test set. A rhodopsin-based model of the human As receptor was built, and the pyridine reference ligand 2,3,4,5-tetraethyl-6-phenyl- pyridine-3-thiocarboxylate-5-carboxylate (MRS 1476) was docked in the putative ligand binding site. Interactions between receptor transmembrane domains and the steric and the electrostatic contour plots obtained from the CoMFA analysis were analyzed.
- Li, An-Hu,Moro, Stefano,Forsyth, Nancy,Melman, Neli,Ji, Xiao-Duo,Jacobson, Kenneth A.
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p. 706 - 721
(2007/10/03)
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- Synthesis of phosphorus-containing amino acid analogs as inhibitors of nitric oxide synthase
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Two series of α-amino phosphonic and α-amino phosphinic analogs of arginine were prepared and tested as inhibitors of nitric oxide synthase (NOS). Two of the analogs were found to possess inhibitory activity for the neuronal isoform of NOS.
- Cowart, Marion,Kowaluk, Elizabeth A.,Kohlhaas, Kathy L.,Alexander, Karen M.,Kerwin Jr., James F.
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p. 999 - 1002
(2007/10/03)
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- A directed amidohalogenation reaction. An unusual reaction of azidoformates
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The thermal intramolecular reaction of an azidoformate and an olefin does not provide the expected aziridine, but rather an amidohalide. This unusual product is formed via an intramolecular nitrene addition to the olefin to initially provide an aziridine.
- Bergmeier,Stanchina
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p. 4533 - 4536
(2007/10/02)
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- A convenient synthesis of N-protected diphenyl phosphonate ester analogues of ornithine, lysine and homolysine
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A 3-step synthesis to the title compounds has been developed which provides them differentially protected at nitrogen. These could then be selectively deprotected using hydrazine hydrate or hydrogenolysis over Pd/C.
- Hamilton,Walker,Walker
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p. 2847 - 2850
(2007/10/02)
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- Total synthesis of nstx-3, spider toxin of Nephila maculata
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A spider toxin NSTX-3 obtained from the venom of Papua New Guinean spider, Nephila maculata was synthesized in order to confirm its proposed structure and to supply the sample for the biological tests. The structure of NSTX-3 is now established as 2,4-dihydroxyphenylacetyl-L-Asn→Cad←Pua←L-Arg, where Cad stands for cadaverine and Pua for putreanine.
- Teshima, Tadashi,Matsumoto, Takahiro,Wakamiya, Tateaki,Shiba, Tetsuo,Aramaki, Yoshio,Nakajima, Terumi,Kawai, Nobufumi
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p. 3305 - 3312
(2007/10/02)
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