- PYRROLOBENZODIAZEPINE DIMER PRECURSOR AND LIGAND-LINKER CONJUGATE COMPOUND THEREOF
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The present invention relates to a pyrrolobenzodiazepine dimer prodrug and a ligand-linker conjugate compound thereof, a composition containing these, and therapeutic use thereof particularly as an anticancer drug. The stability of the compounds themselves and the stability thereof in plasma are excellent and the compounds are advantageous in terms of manifestation of toxicity, and thus the compounds are industrially useful in that it is possible to target proliferative diseases such as cancer, to perform a specific treatment, to maximize the drug efficacy, and to minimize the occurrence of side effects.
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Paragraph 0140; 0141
(2020/02/18)
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- COMPOUNDS COMPRISING CLEAVABLE LINKER AND USES THEREOF
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Provided are a compound including a cleavable linker, a use thereof, and an intermediate compound for preparing the same, and more particularly, the compound including a cleavable linker of the present invention may include an active agent (for example, a drug, a toxin, a ligand, a probe for detection, etc.) having a specific function or activity, a SO2 functional group which is capable of selectively releasing the active agent, and a functional group which triggers a chemical reaction, a physicochemical reaction and/or a biological reaction by external stimulation, and may further include a ligand (for example, oligopeptide, polypeptide, antibody, etc.) having binding specificity for a desired target receptor.
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Page/Page column 189; 190
(2020/07/21)
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- CONJUGATES COMPRISING SELF-IMMOLATIVE GROUPS AND METHODS RELATED THERETO
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In some aspects, the invention relates to an antibody-drug conjugate, comprising an antibody; a linker; and an active agent. The antibody-drug conjugate may comprise a self- immolative group. The linker may comprise an O-substituted oxime, e.g., wherein the oxygen atom of the oxime is substituted with a group that covalently links the oxime to the active agent; and the carbon atom of the oxime is substituted with a group that covalently links the oxime to the antibody.
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Page/Page column 57
(2017/06/27)
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- CONJUGATES COMPRISING PEPTIDE GROUPS AND METHODS RELATED THERETO
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In some aspects, the invention relates to an antibody-drug conjugate, comprising an antibody; a linker; and at least two active agents. In preferred embodiments, the linker comprises a peptide sequence of a plurality of amino acids, and at least two of the active agents are covalently coupled to side chains of the amino acids. The antibody-drug conjugate may comprise a self-immolative group, preferably two-self-immolative groups. The linker may comprise an O-substituted oxime, e.g., wherein the oxygen atom of the oxime is substituted with a group that covalently links the oxime to the active agent; and the carbon atom of the oxime is substituted with a group that covalently links the oxime to the antibody.
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Page/Page column 68
(2017/08/08)
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- Design and synthesis of a series of α-benzyl phenylpropanoic acid-type peroxisome proliferator-activated receptor (PPAR) gamma partial agonists with improved aqueous solubility
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In the continuing study directed toward the development of peroxisome proliferator-activated receptor gamma (hPPARγ) agonist, we attempted to improve the water solubility of our previously developed hPPARγ-selective agonist 3, which is insufficiently soluble for practical use, by employing two strategies: introducing substituents to reduce its molecular planarity and decreasing its hydrophobicity via replacement of the adamantyl group with a heteroaromatic ring. The first approach proved ineffective, but the second was productive. Here, we report the design and synthesis of a series of α-benzyl phenylpropanoic acid-type hPPARγ partial agonists with improved aqueous solubility. Among them, we selected (R)-7j, which activates hPPARγ to the extent of about 65% of the maximum observed with a full agonist, for further evaluation. The ligand-binding mode and the reason for the partial-agonistic activity are discussed based on X-ray-determined structure of the complex of hPPARγ ligand-binding domain (LBD) and (R)-7j with previously reported ligand-LDB structures. Preliminal apoptotic effect of (R)-7j against human scirrhous gastric cancer cell line OCUM-2MD3 is also described.
- Ohashi, Masao,Oyama, Takuji,Putranto, Endy Widya,Waku, Tsuyoshi,Nobusada, Hiromi,Kataoka, Ken,Matsuno, Kenji,Yashiro, Masakazu,Morikawa, Kosuke,Huh, Nam-Ho,Miyachi, Hiroyuki
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p. 2319 - 2332
(2013/05/09)
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- Discovery of nonbenzamidine factor VIIa inhibitors using a biaryl acid scaffold
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In this Letter, we describe the synthesis of several nonamidine analogs of biaryl acid factor VIIa inhibitor 1 containing weakly basic or nonbasic P1 groups. 2-Aminoisoquinoline was found to be an excellent surrogate for the benzamidine group (compound 2) wherein potent inhibition of factor VIIa is maintained relative to most other related serine proteases. In an unanticipated result, the m-benzamide P1 (compounds 21a and 21b) proved to be a viable benzamidine replacement, albeit with a 20-40 fold loss in potency against factor VIIa.
- Bolton, Scott A.,Sutton, James C.,Anumula, Rushith,Bisacchi, Gregory S.,Jacobson, Bruce,Slusarchyk, William A.,Treuner, Uwe D.,Wu, Shung C.,Zhao, Guohua,Pi, Zulan,Sheriff, Steven,Smirk, Rebecca A.,Bisaha, Sharon,Cheney, Daniel L.,Wei, Anzhi,Schumacher, William A.,Hartl, Karen S.,Liu, Eddie,Zahler, Robert,Seiler, Steven M.
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p. 5239 - 5243
(2013/09/12)
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- Design, synthesis and in vitro evaluation of a series of α-substituted phenylpropanoic acid PPARγ agonists to further investigate the stereochemistry-activity relationship
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We previously demonstrated that the α-benzylphenylpropanoic acid-type PPARγ-selective agonist 6 exhibited a reversed stereochemistry-activity relationship, that is, the (R)-enantiomer is a more potent PPARγ agonist than the (S)-enantiomer, compared with s
- Ohashi, Masao,Nobusada, Hiromi,Matsuno, Kenji,Miyachi, Hiroyuki,Nakagome, Izumi,Hirono, Shuichi,Kasuga, Jun-Ichi,Hashimoto, Yuichi,Makishima, Makoto
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p. 6375 - 6383,9
(2012/12/12)
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- Design, synthesis, and structural analysis of phenylpropanoic acid-type PPARγ-selective agonists: Discovery of reversed stereochemistry-activity relationship
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Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-mediated transcription factor with roles in glucose, lipid, and lipoprotein homeostasis, and PPARγ ligands are expected have therapeutic potential in these as well as other areas. We rep
- Ohashi, Masao,Oyama, Takuji,Nakagome, Izumi,Satoh, Mayumi,Nishio, Yoshino,Nobusada, Hiromi,Hirono, Shuichi,Morikawa, Kosuke,Hashimoto, Yuichi,Miyachi, Hiroyuki
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experimental part
p. 331 - 341
(2011/03/22)
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- Design, parallel synthesis, and crystal structures of biphenyl antithrombotics as selective inhibitors of tissue factor FVIIa complex. Part 1: Exploration of S2 pocket pharmacophores
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Factor VIIa (FVIIa), a serine protease enzyme, coupled with tissue factor (TF) plays an important role in a number of thrombosis-related disorders. Inhibition of TF·FVIIa occurs early in the coagulation cascade and might provide some safety advantages over other related enzymes. We report here a novel series of substituted biphenyl derivatives that are highly potent and selective TF·FVIIa inhibitors. Parallel synthesis coupled with structure-based drug design allowed us to explore the S2 pocket of the enzyme active site. A number of compounds with IC50 value of 10 nM were synthesized. The X-ray crystal structures of some of these compounds complexed with TF·FVIIa were determined and results were applied to design the next round of inhibitors. All the potent inhibitors were tested for inhibition against a panel of related enzymes and selectivity of 17,600 over thrombin, 450 over trypsin, 685 over FXa, and 76 over plasmin was achieved. Two groups, vinyl 36b and 2-furan 36ab, were identified as the optimum binding substituents on the phenyl ring in the S2 pocket. Compounds with these two substituents are the most potent compounds in this series with good selectivity over related serine proteases. These compounds will be further explored for structure-activity relationship.
- Kotian, Pravin L.,Krishnan, Raman,Rowland, Scott,El-Kattan, Yahya,Saini, Surendra K.,Upshaw, Ramanda,Bantia, Shanta,Arnold, Shane,Sudhakar Babu,Chand, Pooran
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experimental part
p. 3934 - 3958
(2009/10/02)
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- Design, synthesis, and evaluation of potent, structurally novel peroxisome proliferator-activated receptor (PPAR) δ-selective agonists
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A series of 3-(4-alkoxyphenyl)propanoic acid derivatives was prepared as candidate peroxisome proliferator-activated receptor (PPAR) δ-selective agonists, based on our previously discovered potent human PPARα/δ dual agonist TIPP-401 as a lead compound. Structure-activity relationship studies clearly indicated the importance of the chain length of the alkoxy group at the 4-position, and the n-butoxy compound exhibited the most potent PPARδ transactivation activity and highest PPARδ selectivity. The (S)-enantiomer of a representative compound exhibited extremely potent PPARδ transactivation activity, comparable with or somewhat superior to that of the known PPARδ-selective agonist, GW-501516. The representative compound regulated the expression of genes involved in lipid and glucose homeostasis, and should be useful not only as a chemical tool to study PPARδ function, but also as a candidate drug for the treatment of metabolic syndrome.
- Kasuga, Jun-ichi,Nakagome, Izumi,Aoyama, Atsushi,Sako, Kumiko,Ishizawa, Michiyasu,Ogura, Michitaka,Makishima, Makoto,Hirono, Shuichi,Hashimoto, Yuichi,Miyachi, Hiroyuki
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p. 5177 - 5190
(2008/03/14)
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- Biarylmethyl indolines, indoles and tetrahydroquinolines, useful as serine protease inhibitors
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The present invention provides compounds of Formula (I): or a stereoisomer or pharmaceutically acceptable salt or hydrate form thereof, wherein the variables A, B, L1, L2, X1, X2, X3, X4 an
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- TETRAHYDROQUINOLINE DERIVATIVES USEFUL AS SERINE PROTEASE INHIBITORS
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The present invention provides compounds of Formula (I) ; or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein the variables A, B, L1, L2, X1, X2, X3, X4, R4/su
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- Tetrahydroquinoline derivatives as antithrombotic agents
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This invention relates generally to tetracyclic tetrahydroquinoline compounds, and analogues thereof, and pharmaceutically acceptable salt forms thereof, which are selective inhibitors of serine protease enzymes, especially factor VIIa; pharmaceutical compositions containing the same; and methods of using the same as anticoagulant agents for modulation of the coagulation cascade.
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- Amidino derivatives and drugs containing the same as the active ingredient
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The novel amidino derivatives of the formula (I): wherein all the symbols are as in specification defined; have an inhibitory activity of a blood coagulation factor VIIa and are useful for treatment and/or prevention of several angiopathy caused by enhanc
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Page column 103-104
(2010/01/30)
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- Novel mesogenic benzoic acids with large branches I. Synthesis, liquid crystalline properties and crystal structure analyses of 3-(4-Subst.-benzyloxycarbonyl)-4-(4-n-octyloxybenzoyloxy)benzoic acids
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New benzoyloxybenzoic acids bearing both terminal and lateral groups have been synthesized. Substituted aryl rings are laterally attached to the basic mesogens by means of an odd-numbered spacer. Therefore, liquid crystalline behaviour can be observed at high temperatures. The crystal and molecular structure of 3-(4-cyano-benzyloxycarbonyl)-4-(4-n-octyloxybenzoyloxy)benzoic acid 3b has been determined by X-ray analysis. 3b crystallizes in space group P21/n with four molecules in a unit cell of the following dimensions: a = 15.682(2), b = 7.701(1), c = 23.107(3) A, β = 97.69(1)°. The structure was solved by direct methods and refined to an R value of 0.057 for 3684 observed reflections. The molecules of 3b are associated to dimers with a shape unusual for mesogens exhibiting nematic and smectic phases. In the crystal the dimers are closely packed to ribbons which on their part are connected to lamellar sheets. The nitro-substituted homologue 3c was proved to be isostructural with 3b.
- Weissflog,Dietzmann,Stuetzer,Drewello,Hoffmann,Hartung
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