Synthesis of (3,4-dimethoxyphenoxy)alkylamino acetamides as orexin-2 receptor antagonists.
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.
Cole
Andrew G
AG
Pharmacopeia, Inc., PO Box 5350, Princeton, NJ 08543, USA. acole@pcop.com
Stroke
Ilana L
IL
Qin
Lan-Ying
LY
Hussain
Zahid
Z
Simhadri
Srilatha
S
Brescia
Marc-Raleigh
MR
Waksmunski
Frank S
FS
Strohl
Barbara
B
Tellew
John E
JE
Williams
John P
JP
Saunders
John
J
Appell
Kenneth C
KC
Henderson
Ian
I
Webb
Maria L
ML
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
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