- Fragment Screening of Soluble Epoxide Hydrolase for Lead Generation - Structure-Based Hit Evaluation and Chemistry Exploration
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Soluble epoxide hydrolase (sEH) is involved in the regulation of many biological processes by metabolizing the key bioactive lipid mediator, epoxyeicosatrienoic acids. For the development of sEH inhibitors with improved physicochemical properties, we performed both a fragment screening and a high-throughput screening aiming at an integrated hit evaluation and lead generation. Followed by a joint dose-response analysis to confirm the hits, the identified actives were then effectively triaged by a structure-based hit-classification approach to three prioritized series. Two distinct scaffolds were identified as tractable starting points for potential lead chemistry work. The oxoindoline series bind at the right-hand side of the active-site pocket with hydrogen bonds to the protein. The 2-phenylbenzimidazole-4-sulfonamide series bind at the central channel with significant induced fit, which has not been previously reported. On the basis of the encouraging initial results, we envision that a new lead series with improved properties could be generated if a vector is found that could merge the cyclohexyl functionality of the oxoindoline series with the trifluoromethyl moiety of the 2-phenylbenzimidazole-4-sulfonamide series.
- Xue, Yafeng,Olsson, Thomas,Johansson, Carina A,?ster, Linda,Beisel, Hans-Georg,Rohman, Mattias,Karis, David,B?ckstr?m, Stefan
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Read Online
- Compound serving as thyroid hormone beta receptor agonist and use thereof
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The invention relates to a compound serving as a thyroid hormone beta receptor agonist and use thereof, and further relates to a pharmaceutical composition containing the compound. The compound or thepharmaceutical composition can be used for preparing a
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Paragraph 0271-0272; 0280-0281
(2021/02/10)
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- N-{[2-(PIPERIDIN-1-YL)PHENYL](PHENYL)METHYL}-2-(3-OXO-3,4-DIHYDRO-2H-1,4-BENZOXA ZIN-7-YL)ACETAMIDE DERIVATIVES AND RELATED COMPOUNDS AS ROR-GAMMA MODULATORS FOR TREATING AUTOIMMUNE DISEASES
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The present invention provides e.g. N-{[2-(piperidin-1-yl)phenyl] (phenyl)methyl}-2-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)acetamide derivatives and related compounds as ROR-gamma modulators for treating e.g. autoimmune diseases, autoimmune-related diseases, inflammatory diseases, metabolic diseases, fibrotic diseases or cholestatic diseases, such as e.g. arthitis and asthma.
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Page/Page column 68; 118
(2018/08/20)
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- BICYLIC COMPOUNDS AS MODULATORS OF RORGAMMA
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The present invention encompasses compounds of the formula (I): wherein the variables are defined herein which are suitable for the modulation of RORC and the treatment of diseases related to the modulation of RORC. The present invention also encompasses
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Page/Page column 52; 53
(2015/03/28)
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- Design, synthesis, and SAR of new pyrrole-oxindole progesterone receptor modulators leading to 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)- 1-methyl-1H-pyrrole-2-carbonitrile (WAY-255348)
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We have continued to explore the 3,3-dialkyl-5-aryloxindole series of progesterone receptor (PR) modulators looking for new agents to be used in female healthcare: contraception, fibroids, endometriosis, and certain breast cancers. Previously we reported
- Fensome, Andrew,Adams, William R.,Adams, Andrea L.,Berrodin, Tom J.,Cohen, Jeff,Huselton, Christine,Illenberger, Arthur,Kern, Jeffrey C.,Hudak, Valerie A.,Marella, Michael A.,Melenski, Edward G.,McComas, Casey C.,Mugford, Cheryl A.,Slayden, Ov D.,Yudt, Matthew,Zhang, Zhiming,Zhang, Puwen,Zhu, Yuan,Winneker, Richard C.,Wrobel, Jay E.
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p. 1861 - 1873
(2008/12/20)
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- Thio-oxindole derivatives
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This invention relates to compounds which are agonists of the progesterone receptor which have the general structures: wherein: R1and R2are H, alkyl, substituted alkyl; OH; O(alkyl); O(substituted alkyl); OAc; aryl; substituted aryl; heteroaryl; substituted heteroaryl; alkylaryl; alkylheteroaryl;1-propynyl; or3-propynyl; or R1and R2are joined to form an alkyl, alkenyl or heterocyclic ring; or R1and R2together comprise a double bond to CMe2; C(cycloalkyl), O, or C(cycloether); R3is H, OH, NH2, C1to C6alkyl, substituted C1to C6alkyl, C3to C6alkenyl, alkynyl, substituted alkynyl, or CORA; RAis H, C1to C3alkyl, substituted C1to C3alkyl, C1to C3alkoxy, substituted C1to C3alkoxy, C1to C3aminoalkyl, or substituted C1to C3aminoalkyl; R4is H, halogen, CN, NH2, NO2, C1to C6alkyl, or substituted C1to C6alkyl, C1to C6alkoxy, substituted C1to C6alkoxy, C1to C6aminoalkyl, or substituted C1to C6aminoalkyl; R5is optionally substituted and selected from a benzene ring, a five or six membered heterocyclic ring with 1, 2, or 3 heteroatoms selected from O, S, SO, SO2or NR6; or an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety; Q1is S, NR7, CR8R9; or a pharmaceutically acceptable salt thereof, as well as methods of using these compounds to induce contraception or treat progesterone-related carcinomas and adenocarcinomas.
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Page column 48
(2010/11/30)
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- New progesterone receptor antagonists: 3,3-disubstituted-5-aryloxindoles.
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A new series of 3,3-disubstituted-5-aryloxindoles has been synthesized and evaluated for progesterone receptor antagonist (PR) activity in a T47D cell alkaline phosphatase assay and for their ability to bind PR in competition binding studies. In this comm
- Fensome, Andrew,Bender, Reinhold,Cohen, Jeffrey,Collins, Mark A,Mackner, Valerie A,Miller, Lori L,Ullrich, John W,Winneker, Richard,Wrobel, Jay,Zhang, Puwen,Zhang, Zhiming,Zhu, Yuan
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p. 3487 - 3490
(2007/10/03)
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- Indoline derivatives
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This invention relates to substituted indoline derivative compounds which are antagonists of the progesterone receptor, their preparation and pharmaceutical utility, particularly including contraception and treatment of benign or malignant neoplastic diseases, having the general structure: wherein R1and R2may be single substituents or fused to form spirocyclic rings.
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- CYCLIC REGIMENS UTILIZING INDOLINE DERIVATIVES
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This invention relates to cyclic combination therapies and regimens utilizing substituted indoline derivative compounds which are antagonists of the progesterone receptor having the general structure: wherein R 1 and R 2 may be single substituents or fused to form spirocyclic rings, in combination with progestins, estrogens, or both. These methods of treatment may be used for contraception or for the treatment and/or prevention of secondary amenorrhea, dysfunctional bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, or minimization of side effects or cyclic menstrual bleeding. Additional uses of the invention include stimulation of food intake.
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- 3,3-substituted indoline derivatives
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This invention provides compounds of the formula 1: wherein: R1and R2are chosen independently from each other from H, OH; OAc; alkylaryl; alkylheteroaryl; 1-propynyl; 3-propynyl; and optionally substituted alkyl, O(alkyl); aryl; or h
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- Combination regimens using 3,3-substituted indoline derivatives
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This invention relates to cyclic combination therapies and regimens utilizing substituted indoline derivative compounds that are antagonists of the progesterone receptor having the general structure: wherein: R1, and R2are chosen ind
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- Pharmaceutical compounds
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A pharmaceutical compound of the formula STR1 and salts and esters thereof.
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- Imidazo[4,5-b]pyridyl quinolone cardiac stimulants
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A series of novel heterobicyclic substituted 2-(1H)-quinolone compounds have been prepared, including the 3,4-dihydro derivatives thereof, wherein the heterobicyclic ring moiety is an optionally-substituted indolyl, phthalizinyl, benzimidazolyl, imidazopy
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