- Zn(2+) fluorescent chemosensors and the influence of their spacer length on tuning Zn(2+) selectivity
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Zn(2+) fluorescent chemosensors based on the chelation-enhanced fluorescence (CHEF) mechanism were prepared and fine-tuning of their Zn(2+) selectivity was achieved by control of the spacer length. The fluorescence emission response to metal ions shows a fluorescence decrease for Co(2+), Cu(2+) and Ni(2+) and an increase for Ca(2+), Cd(2+) and Zn(2+). Maximum Zn(2+) selectivity over Ca(2+) and Cd(2+) was achieved with 3. The basic binding properties (stoichiometry, apparent dissociation constant, and pH dependence) were measured by fluorescence spectroscopy. Analysis of the Job plot for the 3-Zn(2+) complex indicates the formation of a 1 :1 complex. The apparent dissociation constant Kd was determined as 0.98 (+/-0.43) nM for 3-Zn(2+) at pH 7.5 [50 mM HEPES buffer I = 0.1 (NaNO3)]. The plateaus in the fluorescence intensity of 2 and the 2-Zn(2+) complex in regions with a pH exceeding 7 imply that the fluorescence measurements should be little affected by physiological pH changes.
- Kim, Tae Woo,Park, Jung-hyun,Hong, Jong-In
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- Supramolecular polymerization of a ureidopyrimidinone-based [2]catenane prepared via ring-closing metathesis
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The synthesis of a Sauvage-type [2]catenane featuring a quadruple hydrogen bonding ureidopyrimidinone (UPy) motif in each ring was reported. Intermolecular dimerization of the UPy motifs induces the hydrogen-bond-driven supramolecular polymerization of the [2]catenane monomer, thereby creating a linear polymer consisting of both hydrogen bonding and mechanical bonds. As the rings in the UPy catenane are asymmetric, two stereoisomers can be formed upon catenation, that is, with the phenanthroline moieties oriented +90° or -90° with respect to each other. Based on the phenanthroline-Cu(I) and ring-closing metathesis (RCM) approach, we first devised a synthetic procedure for the synthesis of the UPy-based catenane. Here, phenanthroline was first functionalized with phenol moieties in a two-step approach with an overall yield of 46%. The resulting biphenol 3 was then alkylated in a statistical manner with a mixture of 4-bromobut-1-ene and t-Boc-protected bromide resulting in t-Boc-protected compound. The results show that protection of the UPy motifs is necessary for this reaction to reach completion. Analysis of the unprotected UPy catenane by 1H NMR revealed the formation of UPy-UPy dimers and significant broadening of the signals, both in presence and absence of Cu(I).
- Teunissen, Abraham J. P.,Berrocal, José Augusto,Corbet, Christiaan H. W. A.,Meijer
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- Gd(III)-nanodiamond conjugates for MRI contrast enhancement
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A Gd(III)-nanodiamond conjugate [Gd(III)-ND] was prepared and characterized, enabling detection of nanodiamonds by MR imaging. The Gd(III)-ND particles significantly reduced the T1 of water protons with a per-Gd(III) relaxlvity of 58.82 ± 1.18 mM-1 s-1 at 1.5 T (60 MHz). This represents a 10-fold increase compared to the monomer Gd(III) complex (r1= 5.42 ± 0.20 mM-1 s -1) and is among the highest per-Gd(III) relaxivities reported.
- Manus, Lisa M.,Mastarone, Daniel J.,Waters, Emily A.,Zhang, Xue-Qing,Schultz-Sikma, Elise A.,MacRenaris, Keith W.,Ho, Dean,Meade, Thomas J.
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- Design and Synthesis of Mercaptoacetamides as Potent, Selective, and Brain Permeable Histone Deacetylase 6 Inhibitors
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A series of nonhydroxamate HDAC6 inhibitors were prepared in our effort to develop potent and selective compounds for possible use in central nervous system (CNS) disorders, thus obviating the genotoxicity often associated with the hydroxamates. Halogens are incorporated in the cap groups of the designed mercaptoacetamides in order to increase brain accessibility. The indole analogue 7e and quinoline analogue 13a displayed potent HDAC6 inhibitory activity (IC50, 11 and 2.8 nM) and excellent selectivity against HDAC1. Both 7e and 13a together with their ester prodrug 14 and disulfide prodrugs 15 and 16 were found to be effective in promoting tubulin acetylation in HEK cells. The disulfide prodrugs 15 and 16 also released a stable concentration of 7e and 13a upon microsomal incubation. Administration of 15 and 16 in vivo was found to trigger an increase of tubulin acetylation in mouse cortex. These results suggest that further exploration of these compounds for the treatment of CNS disorders is warranted.
- Lv, Wei,Zhang, Guangming,Barinka, Cyril,Eubanks, James H.,Kozikowski, Alan P.
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- Dual nicotinamide phosphoribosyltransferase and epidermal growth factor receptor inhibitors for the treatment of cancer
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Multitarget drugs have emerged as a promising treatment modality in modern anticancer therapy. Taking advantage of the synergy of NAMPT and EGFR inhibition, we have developed the first compounds that serve as dual inhibitors of NAMPT and EGFR. On the basis of CHS828 and erlotinib, a series of hybrid molecules were successfully designed and synthesized by merging of the pharmacophores. Among the compounds that were synthesized, compound 28 showed good NAMPT and EGFR inhibition, and excellent in vitro anti-proliferative activity. Compound 28, which is a new chemotype devoid of a Michael receptor, strongly inhibited the proliferation of several cancer cell lines, including H1975 non-small cell lung cancer cells harboring the EGFRL858R/T790M mutation. More importantly, it imparted significant in vivo antitumor efficacy in a human NSCLC (H1975) xenograft nude mouse model. This study provides promising leads for the development of novel antitumor agents and valuable pharmacological probes for the assessment of dual inhibition in NAMPT and EGFR pathway with a single inhibitor.
- Zhang, Wanheng,Zhang, Kuojun,Yao, Yiwu,Liu, Yunyao,Ni, Yong,Liao, Chenzhong,Tu, Zhengchao,Qiu, Yatao,Wang, Dexiang,Chen, Dong,Qiang, Lei,Li, Zheng,Jiang, Sheng
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- OLIGONUCLEOTIDE COMPOSITIONS AND METHODS THEREOF
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The present disclosure provides modified oligonucleotides and compositions and methods thereof. In some embodiments, provided technologies comprise modified sugars and/or modified internucleotidic linkages. In some embodiments, the present disclosure provides technologies for preparing modified oligonucleotides. In some embodiments, the present disclosure provides chirally controlled oligonucleotide compositions and methods for their preparation and uses.
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- THERAPEUTIC METAL COMPLEXES AND LIGANDS AND METHODS OF MAKING AND USING SAME
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Disclosed herein are compound embodiments that are useful for treating a variety of diseases, particularly neurological diseases, motor neuron diseases, copper deficiency-related diseases, and/or mitochondrial deficiencies. The compound embodiments described herein also can be used in PET methods. Also disclosed herein are embodiments of methods of making and using the compound embodiments, as well as pharmaceutical formulations comprising the disclosed compound embodiments.
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- Multifunctional synergistic pharmaceutical composition based on adriamycin and construction method of multifunctional synergistic pharmaceutical composition
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The invention relates to a multifunctional synergistic pharmaceutical composition based on adriamycin. According to the pharmaceutical composition, natural hydrophobic small molecules having a conjugated structure are covalently coupled with a polysaccharide skeleton to form an anti-angiogenesis drug, the anti-angiogenesis drug is physically mixed with the conjugated structure-modifying mitochondria damage peptide derivative and adriamycin, and the pharmaceutical composition of a nano size is assembled by virtue of various supramolecular driving forces. The pharmaceutical composition has the advantages of simultaneously regulating a tumor micro environment and tumor cells, reversing the anti-apoptosis characteristics of tumor cells, and maximizing the antitumor effect of the adriamycin. Inaddition, the multifunctional synergistic pharmaceutical composition has the advantages of the adriamycin such as high load, high stability and high targeting. The multifunctional synergistic pharmaceutical composition based on the adriamycin is compatible with corresponding medicinal auxiliary materials to prepare antitumoar drug preparations for injection, oral administration or external use. The multifunctional synergistic pharmaceutical composition is prepared by virtue of a multi-component supramolecular combination construction, so that the operation is simple, and the industrialized production is easy to realize.
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Paragraph 0074
(2018/05/16)
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- BICYCLIC AND TRICYCLIC CAP BEARING MERCAPTOACETAMIDE DERIVATIVES AS HISTONE DEACETYLASE INHIBITORS
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Histone deacetylases inhibitors (HDACIs) and compositions containing the same are disclosed. Methods of treating diseases and conditions wherein inhibition of HDAC provides a benefit, like a cancer, a neurodegenerative disorder, a peripheral neuropathy, a neurological disease, traumatic brain injury, stroke, hypertension, malaria, an autoimmune disease, autism, autism spectrum disorders, and inflammation, also are disclosed.
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Paragraph 0154; 0157; 0158
(2017/04/11)
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- Towards a characterization of the structural determinants of specificity in the macrocyclizing thioesterase for deoxyerythronolide B biosynthesis
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Type I polyketide synthases (PKSs) are giant multidomain proteins that synthesize many therapeutics and other natural products. The synthesis proceeds by a thiotemplate mechanism whereby intermediates are covalently attached to the PKS. The release of the final polyketide is catalyzed by the terminal thioesterase (TE) domain through hydrolysis, transesterification, or macrocyclization. The PKS 6-deoxyerythronolide B synthase (DEBS) produces the 14-membered macrolide core of the clinically important antibiotic erythromycin. The TE domain of DEBS (DEBS TE) has well-established, empirically-defined specificities for hydrolysis or macrocyclization of native and modified substrates. We present efforts towards understanding the structural basis for the specificity of the thioesterase reaction in DEBS TE using a set of novel diphenyl alkylphosphonates, which mimic substrates that are specifically cyclized or hydrolyzed by DEBS TE. We have determined structures of a new construct of DEBS TE alone at 1.7 ?, and DEBS TE bound with a simple allylphosphonate at 2.1 ? resolution. Other, more complex diphenyl alkylphosphonates inhibit DEBS TE, but we were unable to visualize these faithful cyclization analogs in complex with DEBS TE. This work represents a first step towards using DEBS TE complexed with sophisticated substrate analogs to decipher the specificity determinants in this important reaction.
- Argyropoulos, Panos,Bergeret, Fabien,Pardin, Christophe,Reimer, Janice M.,Pinto, Atahualpa,Boddy, Christopher N.,Schmeing, T. Martin
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p. 486 - 497
(2016/02/05)
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- NOVEL PRODRUGS OF DITHIOL MUCOLYTIC AGENTS
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Provided are mucolytic compounds that are more effective, and/or absorbed less rapidly from mucosal surfaces, and/or are better tolerated as compared to N-acetylcysteine (NAC) and DTT. The compounds are represented by compounds of Formula I which embrace structures (la)-(Ib), where the structural variables are as defined herein.
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- Paramagnetic metal-nanodiamond conjugates
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The present invention provides compositions and methods for the synthesis of conjugates of paramagnetic metal ions and nanodiamonds, and uses thereof. In particular, the present invention provides synthesis of paramagnetic metal-nanodiamond conjugates and methods using such compositions as molecular imaging probes.
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- AUTOTAXIN INHIBITOR COMPOUNDS
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Described herein are compounds that are autotaxin inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorde
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Paragraph 00400
(2015/06/08)
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- Thiol-based potent and selective HDAC6 inhibitors promote tubulin acetylation and T-regulatory cell suppressive function
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Several new mercaptoacetamides were synthesized and studied as HDAC6 inhibitors. One compound, 2b, bearing an aminoquinoline cap group, was found to show 1.3 nM potency at HDAC6, with >3000-fold selectivity over HDAC1. 2b also showed excellent efficacy at increasing tubulin acetylation in rat primary cortical cultures, inducing a 10-fold increase in acetylated tubulin at 1 μM. To assess possible therapeutic effects, compounds were assayed for their ability to increase T-regulatory (Treg) suppressive function. Some but not all of the compounds increased Treg function, and thereby decreased conventional T cell activation and proliferation in vitro.
- Segretti, Mariana C. F.,Vallerini, Gian Paolo,Brochier, Camille,Langley, Brett,Wang, Liqing,Hancock, Wayne W.,Kozikowski, Alan P.
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supporting information
p. 1156 - 1161
(2015/11/25)
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- MACROCYCLIC COMPOUNDS AS IRAK4 INHIBITORS FOR THE TREATMENT OF INFLAMMATORY DISEASES
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Provided are compounds of Formula (I), or pharmaceutically acceptable salts thereof, wherein i.a. Ring A is phenylene or 5- to 6-membered heteroarylene; Ring B is phenylene, 5- to 6-membered heterocycloalkylene or 5- to 6-membered heteroarylen; R4/s
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Paragraph 0283
(2014/09/29)
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- PARAMAGNETIC METAL-NANODIAMOND CONJUGATES
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The present invention provides compositions and methods for the synthesis of conjugates of paramagnetic metal ions and nanodiamonds, and uses thereof. In particular, the present invention provides synthesis of paramagnetic metal-nanodiamond conjugates and methods using such compositions as molecular imaging probes.
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- Fluoroalkene modification of mercaptoacetamide-based histone deacetylase inhibitors
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Inhibitors of histone deacetylases (HDAC) are emerging as a promising class of anti-cancer agents. The mercaptoacetoamide-based inhibitors are reported to be less toxic than hydroxamate and are worthy of further consideration. Therefore, we have designed a series of analogs as potential inhibitors of HDACs, in which the mercaptoacetamide group was replaced by (mercaptomethyl)fluoroalkene, and their HDAC inhibitory activity was evaluated. Subnanomolar inhibition was observed for all synthetic compounds.
- Osada, Satoshi,Sano, Satoshi,Ueyama, Mariko,Chuman, Yoshiro,Kodama, Hiroaki,Sakaguchi, Kazuyasu
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experimental part
p. 605 - 611
(2010/05/02)
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- Design, synthesis, and biological activity of folate receptor-targeted prodrugs of thiolate histone deacetylase inhibitors
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Aiming to develop selective anticancer drugs, we designed and synthesized three disulfides bearing a folic acid moiety as candidate folate receptor (FR)-targeted prodrugs of thiolate histone deacetylase inhibitors. Among them, compound 1 displayed growth-inhibitory activity toward folate receptor-positive MCF-7 breast cancer cells. The activity of 1 was significantly reduced by free folic acid, suggesting that cellular uptake of 1 is mediated by FR.
- Suzuki, Takayoshi,Hisakawa, Shinya,Itoh, Yukihiro,Suzuki, Nobuaki,Takahashi, Katsumasa,Kawahata, Masatoshi,Yamaguchi, Kentaro,Nakagawa, Hidehiko,Miyata, Naoki
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p. 4208 - 4212
(2008/02/12)
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- Therapeutic compounds for inhibiting interleukin-12 signals and method for using same
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Novel heterocyclic compounds having a six membered ring structure fused to a five membered ring structure are found to be useful for the treatment and prevention of symptoms or manifestations associated with disorders affected by Interleukin-12 (“IL-12”) intracellular signaling, such as, for example, Th1 cell-mediated disorders. The therapeutic compounds, pharmaceutically acceptable derivatives (e.g., resolved enantiomers, diastereomers, tautomers, salts and solvates thereof) or prodrugs thereof, have the following general formula: Each X, Y and Z are independently selected from a member of the group consisting of C(R3), N, N(R3) and S. Each R1, R2 and R3 is substituted or unsubstituted and is independently selected from a member of the group consisting of hydrogen, halo, oxo, C(1-20)alkyl, C(1-20)hydroxyalkyl, C(1-20)thioalkyl, C(1-20)alkylamino, C(1-20)alkylaminoalkyl, C(1-20)aminoalkyl, C(1-20)aminoalkoxyalkenyl, C(1-20)aminoalkoxyalkynyl, C(1-20)diaminoalkyl, C(1-20)triaminoalkyl, C(1-20)tetraaminoalkyl, C(5-15)aminotrialkoxyamino, C(1-20)alkylamido, C(1-20)alkylamidoalkyl, C(1-20)amidoalkyl, C(1-20)acetamidoalkyl, C(1-20)alkenyl, C(1-20)alkynyl, C(3-8)alkoxyl, C(1-11)alkoxyalkyl, and C(1-20)dialkoxyalkyl.
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- Utilizing the intramolecular Fukuyama-Mitsunobu reaction for a flexible synthesis of novel heterocyclic scaffolds for peptidomimetic drug design
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We report the synthesis of the novel scaffolds pyrazino[1,2-b]isoquinoline and pyrrolo[1,2-a]pyrazine displaying the somatostatin pharmacophores. Both classes of compounds contain a pyrazine heterocycle, which can be prepared in a straightforward manner utilizing an intramolecular Fukuyama-Mitsunobu reaction. As both the families derive from amino acids, they can be accessed in high optical purity.
- Zapf, Christoph W.,Del Valle, Juan R.,Goodman, Murray
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p. 4033 - 4036
(2007/10/03)
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- Therapeutic compounds for inhibiting interleukin-12 signaling and methods for using same
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Novel heterocyclic compounds having a six membered ring structure fused to a five membered ring structure are found to be useful for the treatment and prevention of symptoms or manifestations associated with disorders affected by Interleukin-12 (“IL-12”) intracellular signaling, such as, for example, Th1 cell-mediated disorders. The therapeutic compounds, pharmaceutically acceptable derivatives (e.g., resolved enantiomers, diastereomers, tautomers, salts and solvates thereof) or prodrugs thereof, have the following general formula: Each X, Y and Z are independently selected from a member of the group consisting of C(R3), N, N(R3) and S. Each R1, R2 and R3 is substituted or unsubstituted and is independently selected from a member of the group consisting of hydrogen, halo, oxo, C(1-20)alkyl, C(1-20)hydroxyalkyl, C(1-20)thioalkyl, C(1-20)alkylamino, C(1-20)alkylaminoalkyl, C(1-20)aminoalkyl, C(1-20)aminoalkoxyalkenyl, C(1-20)aminoalkoxyalkynyl, C(1-20)diaminoalkyl, C(1-20)triaminoalkyl, C(1-20)tetraaminoalkyl, C(5-15)aminotrialkoxyamino, C(1-20)alkylamido, C(1-20)alkylamidoalkyl, C(1-20)amidoalkyl, C(1-20)acetamidoalkyl, C(1-20)alkenyl, C(1-20)alkynyl, C(3-8)alkoxyl, C(1-11)alkoxyalkyl, and C(1-20)dialkoxyalkyl.
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- THERAPEUTIC COMPOUNDS FOR INHIBITING INTERLEUKIN-12 SIGNALING AND METHODS FOR USING SAME
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Novel heterocyclic compounds having a six membered ring structure fused to a five membered ring structure are found to be useful for the treatment and prevention of symptoms or manifestations associated with disorders affected by Interleukin-12 (“IL-12”) intracellular signaling, such as, for example, Th1 cell-mediated disorders. The therapeutic compounds, pharmaceutically acceptable derivatives (e.g., resolved enantiomers, diastereomers, tautomers, salts and solvates thereof) or prodrugs thereof, have the following general formula: Each X, Y and Z are independently selected from a member of the group consisting of C(R3), N, N(R3) and S. Each R1, R2 and R3 is substituted or unsubstituted and is independently selected from a member of the group consisting of hydrogen, halo, oxo, C(1-20)alkyl, C(1-20)hydroxyalkyl, C(1-20)thioalkyl, C(1-20)alkylamino, C(1-20)alkylaminoalkyl, C(1-20)aminoalkyl, C(1-20)aminoalkoxyalkenyl, C(1-20)aminoalkoxyalkynyl, C(1-20)diaminoalkyl, C(1-20)triaminoalkyl, C(1-20)tetraaminoalkyl, C(5-15)aminotrialkoxyamino, C(1-20)alkylamido, C(1-20)alkylamidoalkyl, C(1-20)amidoalkyl, C(1-20)acetamidoalkyl, C(1-20)alkenyl, C(1-20)alkynyl, C(3-8)alkoxyl, C(1-11)alkoxyalkyl, and C(1-20)dialkoxyalkyl.
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- Non-Peptide Fibrinogen Receptor Antagonists. 2. Optimization of a Tyrosine Template as a Mimic for Arg-Gly-Asp
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Inhibitors of platelet-fibrinogen binding offer an opportunity to interrupt the final, common pathway for platelet aggregation.Small molecule inhibitors of the platelet fibrinogen receptor GPIIb/IIIa were prepared and evaluated for their ability to prevent platelet aggregation.Compound 23m (L-700, 462/MK-383) inhibited in vitro platelet aggregation with an IC50 of 9 nM and demonstrated a selectivity of >24000-fold between platelet and human umbilical vein endothelial cell fibrinogen receptors.Dose-dependent inhibition of ex vivo platelet aggregation induced by ADP was achieved with iv infusions 0.1-10 μg/kg/min of 23m in anesthetized dogs, with 10 μg/kg/min completely inhibiting platelet aggregation during the entire 6 h infusion protocol.Platelet aggregatability returned rapidly after the termination of the 23m infusions.These features suggest that 23m may be useful in the treatment of arterial occlusive disorders.
- Egbertson, Melissa S.,Chang, Charles T.-C.,Duggan, Mark E.,Gould, Robert J.,Halczenko, Wasyl,et al.
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p. 2537 - 2551
(2007/10/02)
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