1112851-31-6Relevant articles and documents
Nobiletin derivative or pharmaceutically acceptable salt thereof as well as preparation method and application thereof
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, (2019/12/09)
The invention discloses a nobiletin derivative or a pharmaceutically acceptable salt thereof as well as a preparation method and application thereof. The nobiletin derivative has a structural formula(I) shown in the description, in the formula, R1, R2, R3 and R4 are respectively selected from hydrogen, halogen, hydroxyl, amino, C1-6 substituted or non-substituted alkoxy, a C1-6 substituted or non-substituted ester group, C1-6 substituted or non-substituted alkamino and a C1-6 substituted or non-substituted amide group; R5 is selected from a C3-9 substituted or non-substituted aromatic ring and a C3-9 substituted or non-substituted aromatic heterocyclic ring; and X is selected from O or NR6. The nobiletin derivative or the pharmaceutically acceptable salt thereof, which is disclosed by theinvention, is novel in structure, and in addition, the compound has an excellent inhibition function on P-gp, can be prepared into a P-gp inhibitor, is capable of treating and/or preventing related diseases caused by P-gp, particularly diseases related to tumor drug resistance, or can be mixed and used with other medicines and used as a drug resistance reversal agent, has a high reversion multiple, and is capable of remarkably improving medicine effects of medicines.
Discovery of 5″-chloro-n-[(5,6-dimethoxypyridin-2- yl)methyl]-2,2':5',3″-Terpyridine-3'-carboxamide (mk-1064): A selective orexin 2 receptor antagonist (2-sora) for the treatment of insomnia
Roecker, Anthony J.,Mercer, Swati P.,Schreier, John D.,Cox, Christopher D.,Fraley, Mark E.,Steen, Justin T.,Lemaire, Wei,Bruno, Joseph G.,Harrell, C. Meacham,Garson, Susan L.,Gotter, Anthony L.,Fox, Steven V.,Stevens, Joanne,Tannenbaum, Pamela L.,Prueksaritanont, Thomayant,Cabalu, Tamara D.,Cui, Donghui,Stellabott, Joyce,Hartman, George D.,Young, Steven D.,Winrow, Christopher J.,Renger, John J.,Coleman, Paul J.
, p. 311 - 322 (2014/04/03)
The field of small-molecule orexin antagonist research has evolved rapidly in the last 15 years from the discovery of the orexin peptides to clinical proof-of-concept for the treatment of insomnia. Clinical programs have focused on the development of antagonists that reversibly block the action of endogenous peptides at both the orexin 1 and orexin 2 receptors (OX1R and OX2R), termed dual orexin receptor antagonists (DORAs), affording late-stage development candidates including Merck's suvorexant (new drug application filed 2012). Full characterization of the pharmacology associated with antagonism of either OX1R or OX2R alone has been hampered by the dearth of suitable subtype-selective, orally bioavailable ligands. Herein, we report the development of a selective orexin 2 antagonist (2-SORA) series to afford a potent, orally bioavailable 2-SORA ligand. Several challenging medicinal chemistry issues were identified and overcome during the development of these 2,5-disubstituted nicotinamides, including reversible CYP inhibition, physiochemical properties, P-glycoprotein efflux and bioactivation. This article highlights structural modifications the team utilized to drive compound design, as well as in vivo characterization of our 2-SORA clinical candidate, 5''-chloro-N- [(5,6-dimethoxypyridin-2-yl)methyl] -2,2':5',3''-terpyridine-3'-carboxamide (MK-1064), in mouse, rat, dog, and rhesus sleep models.
ISONICOTINAMIDE OREXIN RECEPTOR ANTAGONISTS
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Page/Page column 49, (2010/05/14)
The present invention is directed to isonicotinamide compounds which are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. Th
