title: Synthesis of (3,4-dimethoxyphenoxy)alkylamino acetamides as orexin-2 receptor antagonists.
abstract: The discovery and synthesis of a series of (dimethoxyphenoxy)alkylamino acetamides as orexin-2 receptor antagonists from a small-molecule combinatorial library using a high-throughput calcium mobilization functional assay (HEK293-human OX2-R cell line) is described. Active compounds show a good correlation between high-throughput single concentration screening data and measured IC(50)s. Specific examples exhibit IC(50) values of approximately 20 nM using human orexin A as the peptide agonist for the orexin-2 receptor.
authors.affiliation: Pharmacopeia, Inc., PO Box 5350, Princeton, NJ 08543, USA. acole@pcop.com
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Cole
authors.forename: Ilana L
authors.initials: IL
authors.lastname: Stroke
authors.forename: Lan-Ying
authors.initials: LY
authors.lastname: Qin
authors.forename: Zahid
authors.initials: Z
authors.lastname: Hussain
authors.forename: Srilatha
authors.initials: S
authors.lastname: Simhadri
authors.forename: Marc-Raleigh
authors.initials: MR
authors.lastname: Brescia
authors.forename: Frank S
authors.initials: FS
authors.lastname: Waksmunski
authors.forename: Barbara
authors.initials: B
authors.lastname: Strohl
authors.forename: John E
authors.initials: JE
authors.lastname: Tellew
authors.forename: John P
authors.initials: JP
authors.lastname: Williams
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Appell
authors.forename: Ian
authors.initials: I
authors.lastname: Henderson
authors.forename: Maria L
authors.initials: ML
authors.lastname: Webb
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry; D002118:Calcium / Q000737:chemistry; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry*; D008956:Models, Chemical; D009154:Mutation; D009479:Neuropeptides / Q000737:chemistry*; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*; D013696:Temperature
chemical_list: D000081:Acetamides; C000596229:HCRT protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D002118:Calcium