Synthesis of (3,4-dimethoxyphenoxy)alkylamino acetamides as orexin-2 receptor antagonists

The Hypocretin/Orexin System: An Increasingly Important Role in Neuropsychiatry

“…Asahi et al found that replacement of alanine and leucine in sites 11 and 15 in orexin‐B increased its affinity to its receptors and induced Ca 2+ elevation in CHO cells . On the other hand, since the first OX 2 receptor inhibitor, N‐Acyl 6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinoline, was developed by Masaaki et al., lots of researchers tried hard to explore nonpeptide antagonists of OX 2 receptors, such as substituted 4‐phenyl‐[1,3]dioxanes series, (3,4‐dimethoxyphenoxy)alkylamino acetamides, N ‐ethyl‐2‐[(6‐methoxy‐pyridin‐3‐yl)‐(toluene‐2‐sulphonyl)‐amino]‐ N ‐pyridin‐3‐ylmethyl‐ acetamide (EMPA), 2‐methyl‐3‐furanyl‐4H‐1,2,4‐triazol‐3‐ylthioamides, benzoxazepine‐based compound 1a, spiropiperidine‐based compound 4f, and 2,5‐diarylnicotinamides . Moreover, administration of TCSOX229, antagonist of OX 2 receptor, elicited increase of REM sleep and reduced wakefulness .…”

Comprehensive Survey of Chemical Libraries for Drug Discovery and Chemical Biology: 2008

“…OX2 Receptor Antagonists. 104 The orexins (orexin A and orexin B, also named hypocretin 1 and 2, respectively) are hypothalamic peptides playing an important role in the regulation of the sleep-wake cycle, feeding behavior, regulation of gastric acid secretion, metabolic rate and 285 The majority of drugs that target GPCRs interact with the receptor orthosteric site (i.e., the same domain recognized by the endogenous agonist for the receptor). Recently, several research groups identified ligands binding to allosteric sites of GPCRs (i.e., binding domains topographically distinct from the orthosteric sites).…”

“…Polymer-supported reagents/scavengers/linkers are presented in Tables (nonfluorous) and Table (fluorous). There are 505 libraries and 30 molecular probes extracted from 490 literature citations. − …”

“…There are 26 vignettes in the 2008 literature review. Selected vignettes on biologically active libraries include HIV-1 nonnucleoside reverse transcriptase inhibitors, Aurora A kinase inhibitors, orexin-2 receptor antagonists, mGluR4 allosteric modulators, p38α kinase inhibitors, TACE inhibitors, cannabinoid-2 receptor agonists, CCR2b receptor antagonists, and DOS-derived MRSA growth inhibitors . The molecular probe selections include: dapagliflozin, dorsomorphin, a neuregulin/ErbB4 signaling inhibitor, and proteinase activated receptor-2 (PAR-2) agonist AC-262613 .…”