- Enhancing endogenous adenosine A2A receptor signaling induces slow-wave sleep without affecting body temperature and cardiovascular function
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Insomnia is one of the most common sleep problems with an estimated prevalence of 10%–15% in the general population. Although adenosine A2A receptor (A2AR) agonists strongly induce sleep, their cardiovascular effects preclude their use in treating sleep disorders. Enhancing endogenous A2AR signaling, however, may be an alternative strategy for treating insomnia, because adenosine levels in the brain accumulate during wakefulness. In the present study, we found that 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid, denoted A2AR positive allosteric modulator (PAM)-1, enhanced adenosine signaling at the A2AR and induced slow wave sleep (SWS) without affecting body temperature in wild-type male mice after intraperitoneal administration, whereas the SWS-inducing effect of this benzoic acid derivative was abolished in A2AR KO mice. In contrast to the A2AR agonist CGS 21680, the A2AR PAM-1 did not affect blood pressure or heart rate. These findings indicate that enhancing A2AR signaling promotes SWS without cardiovascular effects. Therefore, small molecules that allosterically modulate A2ARs could help people with insomnia to fall asleep.
- Korkutata, Mustafa,Saitoh, Tsuyoshi,Cherasse, Yoan,Ioka, Shuji,Duo, Feng,Qin, Rujie,Murakoshi, Nobuyuki,Fujii, Shinya,Zhou, Xuzhao,Sugiyama, Fumihiro,Chen, Jiang-Fan,Kumagai, Hidetoshi,Nagase, Hiroshi,Lazarus, Michael
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Read Online
- MODIFIED PROTEINS AND PROTEIN DEGRADERS
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Provided herein are compounds, pharmaceutical compositions, and methods for binding or degrading target proteins. Further provided herein are compounds having a DNA damage-binding protein 1 (DDB1) binding moiety. Some such embodiments include a linker. Some such embodiments include a target protein binding moiety. Further provided herein are ligand-DDB1 complexes. Further provided herein are in vivo modified DDB1 proteins.
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Paragraph 001363-001365
(2021/12/08)
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- Crystalline solids of MEK inhibitor N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof
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The present disclosure relates to a) crystalline forms of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; b) pharmaceutical compositions comprising one or more crystalline forms of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and, optionally, one or more pharmaceutically acceptable carriers; c) methods of treating a tumor a cancer, or a Rasopathy disorder by administering one or more crystalline forms of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide to a subject in need thereof, and methods of producing essentially pure Form IV of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
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Page/Page column 94; 96; 99-101
(2021/08/11)
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- Compositions of essentially pure form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof
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The present disclosure relates to: a) a crystalline composition of essentially pure Form IV of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; b) pharmaceutical compositions comprising the crystalline composition of essentially pure Form IV of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and, optionally, a pharmaceutically acceptable carrier; and c) methods of treating a tumor, a cancer, or a Rasopathy disorder by administering the crystalline composition of essentially pure Form IV of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide to a subject in need thereof.
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Page/Page column 21-22
(2021/07/21)
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- NOVEL SLOW-WAVE SLEEP INDUCING AGENT
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PROBLEM TO BE SOLVED: To provide a sleep inducing agent that induces slow-wave sleep (SWS) without causing side effects such as a cardiovascular action. SOLUTION: A slow-wave sleep inducing agent is provided that includes a compound represented by formula (I) or pharmaceutically acceptable salt thereof (R1 is a carboxyl group; m R2 independently represent a halogen atom, an alkyl group, a nitro group, an alkoxy group, a cyano group or an aryl group; n R3 independently represent a halogen atom, an alkyl group, a nitro group, an alkoxy group, a cyano group or an aryl group; m is 0, 1 or 2; n is 1 or 2). SELECTED DRAWING: None COPYRIGHT: (C)2019,JPOandINPIT
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Paragraph 0065; 0066; 0067; 0068
(2019/07/29)
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- A cappi for nepal chemical synthesis method
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The invention belongs to the field of chemical synthesis and specifically relates to a preparation method for cobimetinib. The method comprises the following steps: by taking 2,3,4-benzyl trifluorobenzoate as an initial raw material, performing substitution reaction, deprotection reaction, amidation reaction and catalytic addition reaction, thereby obtaining the cobimetinib. The method provided by the invention has the advantages of easily-obtained and low-cost raw materials, short process flow, easiness in operation of industrial reaction, high yield, environmental protection and suitability for industrial batch production.
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Paragraph 0050-0052
(2018/01/13)
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- NOVEL ANTHRANILIC AMIDES AND THE USE THEREOF
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Disclosed are anthranilic amide derivatives having the formula. Compositions are disclosed that include the anthranilic amide derivatives and the use of the anthranilic amide derivatives for the manufacture of a medicament. Further disclosed are methods of inhibiting or treating cancer, inhibiting or reversing an epithelial to mesenchymal cellular transition, and/or inhibiting MEKI/2 and/or MEK 5 enzymatic activity in a subject by administering to the subject an effective amount of a disclosed anthranilic amide derivative.
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Paragraph 0141; 0142
(2015/03/28)
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- CARBOXYLIC ACID ESTER PRODRUG INHIBITORS OF MEK
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The invention generally relates to compounds having structure I: wherein x represents alkyl, aryl or het-aryl, each of y independently represents hydrogen or halogen and z represents hydrogen or alkyl. Further, said compounds are inhibitors of MEK 1, 2 and 5. Furthermore, the invention includes methods of making said compounds, compositions including said compounds and uses for inhibiting MEK 1, 2 and 5.
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Paragraph 0020
(2014/05/20)
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- Design and synthesis of minimalist terminal alkyne-containing diazirine photo-crosslinkers and their incorporation into kinase inhibitors for cell- and tissue-based proteome profiling
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Less is more: A minimalist "clickable" photo-crosslinker (see scheme) was incorporated with numerous small-molecule kinase inhibitors. The resulting probes were used for both in vitro (cell lysates) and in situ (live cells) proteome profiling, for large-scale identification of their potential cellular kinase targets and shows improved outcomes over previous probes. Copyright
- Li, Zhengqiu,Hao, Piliang,Li, Lin,Tan, Chelsea Y. J.,Cheng, Xiamin,Chen, Grace Y. J.,Sze, Siu Kwan,Shen, Han-Ming,Yao, Shao Q.
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supporting information
p. 8551 - 8556
(2013/09/12)
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- The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901
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A novel series of benzhydroxamate esters derived from their precursor anthranilic acids have been prepared and have been identified as potent MEK inhibitors. 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzam ide, CI-1040, was the first MEK inhibitor to demonstrate in vivo activity in preclinical animal models and subsequently became the first MEK inhibitor to enter clinical trial. CI-1040 suffered however from poor exposure due to its poor solubility and rapid clearance, and as a result, development of the compound was terminated. Optimization of the diphenylamine core and modification of the hydroxamate side chain for cell potency, solubility, and exposure with oral delivery resulted in the discovery of the clinical candidate N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-b enzamide PD 0325901.
- Barrett, Stephen D.,Bridges, Alexander J.,Dudley, David T.,Saltiel, Alan R.,Fergus, James H.,Flamme, Cathlin M.,Delaney, Amy M.,Kaufman, Michael,LePage, Sophie,Leopold, Wilbur R.,Przybranowski, Sally A.,Sebolt-Leopold, Judith,Van Becelaere, Keri,Doherty, Annette M.,Kennedy, Robert M.,Marston, Dan,Howard Jr., W. Allen,Smith, Yvonne,Warmus, Joseph S.,Tecle, Haile
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scheme or table
p. 6501 - 6504
(2009/10/01)
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- METHODS OF PREPARING MEK INHIBITOR
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This invention relates to methods of preparing MEK inhibitor N-[(R)-2,3-dihydroxy-propoxy]-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide that useful for treating diseases mediated by MEK activity in mammals. The present invention provides new synthetic routes that are safe, efficient and cost effective when carried out on a commercial scale.
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Page/Page column 13-14
(2008/06/13)
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- MEK INHIBITING OXA- AND THIA-DIAZOL-2-YL PHENYLAMINE DERIVATES
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This invention provides substituted Phenyl-(2-[1,3,4]thiadiazol-2-yl-phenyl)-amine and (2-[1,3,4]Oxadiazol-2-yl-phenyl)phenyl-amine compounds which act as inhibitors of MAPKIERK Kinase ("MEK") enzymes and pharmaceutical compositions and methods for their use in immunomodulation and in the treatment and alleviation of inflammation, and proliferative diseases such as cancer and restenosis.
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Page 16; 23-24; 28; 31-32; 37-38
(2010/02/07)
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- Process for making n-aryl-anthranilic acids and their derivatives
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The present invention relates to a process for the preparation of N-arylanthranilic acids, and a process for the preparation of N-aryl anthranilic esters, amides, and hydroxamic esters.
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