- Synthesis and biological evaluation of thielocin B1 analogues as protein-protein interaction inhibitors of PAC3 homodimer
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The synthesis and biological evaluation of thielocin B1 analogues have been demonstrated. Fourteen analogues modified in the central core and terminal carboxylic acid moiety were concisely synthesized by simple esterification or etherification reaction. The evaluation of synthetic analogues as inhibitors of proteasome assembling chaperone (PAC) complexes (the PAC3 homodimer and PAC1/PAC2) revealed that the natural product-like bending structure and terminal carboxylic acid groups were crucial for its biological activity. Moreover, SAR and in silico docking studies indicated that all methyl groups on the diphenyl ether moiety of thielocin B1 contribute to the potent and selective inhibition of the PAC3 homodimer via hydrophobic interactions.
- Ohsawa, Kosuke,Yoshida, Masahito,Izumikawa, Miho,Takagi, Motoki,Shin-ya, Kazuo,Goshima, Naoki,Hirokawa, Takatsugu,Natsume, Tohru,Doi, Takayuki
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supporting information
p. 6023 - 6034
(2018/11/23)
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- Discovery of ONO-7300243 from a Novel Class of Lysophosphatidic Acid Receptor 1 Antagonists: From Hit to Lead
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Lysophosphatidic acid (LPA) evokes various physiological responses through a series of G protein-coupled receptors known as LPA1-6. A high throughput screen against LPA1 gave compound 7a as a hit. The subsequent optimization of 7a led to ONO-7300243 (17a) as a novel, potent LPA1 antagonist, which showed good efficacy in vivo. The oral dosing of 17a at 30 mg/kg led to reduced intraurethral pressure in rats. Notably, this compound was equal in potency to the α1 adrenoceptor antagonist tamsulosin, which is used in clinical practice to treat dysuria with benign prostatic hyperplasia (BPH). In contrast to tamsulosin, compound 17a had no impact on the mean blood pressure at this dose. These results suggest that LPA1 antagonists could be used to treat BPH without affecting the blood pressure. Herein, we report the hit-to-lead optimization of a unique series of LPA1 antagonists and their in vivo efficacy.
- Terakado, Masahiko,Suzuki, Hidehiro,Hashimura, Kazuya,Tanaka, Motoyuki,Ueda, Hideyuki,Kohno, Hiroshi,Fujimoto, Taku,Saga, Hiroshi,Nakade, Shinji,Habashita, Hiromu,Takaoka, Yoshikazu,Seko, Takuya
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supporting information
p. 913 - 918
(2016/10/22)
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- THERAPEUTIC INHIBITORY COMPOUNDS
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The invention provides compounds of Formula I and Formula II: A-B-C-D-E-F-G-J (I) C-D-E-F-G-J (II) wherein A, B, C, D, E, F, G, and J have any of the values defined in the specification, and salts thereof. The compounds are useful for inhibiting plasma kallikrein, and for treating a disease or condition in an animal where inhibition of plasma kallikrein is indicated.
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Page/Page column 80
(2015/07/16)
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- Pyrazole[3,4-e][1,4]thiazepin-7-one derivatives as a novel class of Farnesoid X Receptor (FXR) agonists
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A virtual screening procedure was applied to the discovery of structurally diverse non-steroidal Farnesoid X Receptor (FXR) agonists. From 117 compounds selected by virtual screening, a total of 47 compounds were found to be FXR agonists, with 34 of them showing activity below a concentration of 20 μM. 1H-Pyrazole[3,4-e][1,4]thiazepin-7-one-based hit compound 7 was chosen for hit-to-lead optimization. A large number of 1H-pyrazole[3,4-e][1,4]thiazepin-7- one derivatives was designed, synthesized, and evaluated by a cell-based luciferase transactivation assay for their agonistic activity against FXR. Most of them exhibited low micromolar range of potency and very high efficacy.
- Marinozzi, Maura,Carotti, Andrea,Sansone, Emanuele,MacChiarulo, Antonio,Rosatelli, Emiliano,Sardella, Roccaldo,Natalini, Benedetto,Rizzo, Giovanni,Adorini, Luciano,Passeri, Daniela,De Franco, Francesca,Pruzanski, Mark,Pellicciari, Roberto
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supporting information; experimental part
p. 3429 - 3445
(2012/07/30)
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- NOVEL BRADYKININ B1-ANTAGONISTS
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The present invention relates to compounds of general formula I wherein n, R1, R2, R3, R4, R5, R6, R7 and R8 are defined as stated hereinafter, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases, which have valuable properties, the preparation thereof, the pharmaceutical compositions containing the pharmacologically effective compounds, the preparation thereof and the use thereof.
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Page/Page column 47
(2011/11/06)
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