Identifying structural features on 1,1-diphenyl-hexahydro-oxazolo[3,4-a]pyrazin-3-ones critical for Neuropeptide S antagonist activity.
A series of 7-substituted 1,1-diphenyl-hexahydro-oxazolo[3,4-a]pyrazin-3-ones were synthesized and tested for Neuropeptide S (NPS) antagonist activity. A concise synthetic route was developed, which features a DMAP catalyzed carbamate formation. 4-Fluorobenzyl urea (1c) and benzyl urea (1d) were identified as the most potent antagonists among the compounds examined. Structure-activity relationships (SARs) demonstrate that a 7-position urea functionality is required for potent antagonist activity and alkylation of the urea nitrogen (1e) or replacement with carbon or oxygen (5a) results in reduced potency. In addition, compounds with alpha-methyl substitution (1b) or elongated alkyl chains (1h and 1j) had reduced potency, indicating a limited tolerance for 7-position substituents.
Organic and Medicinal Chemistry, Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709, USA.
Yanan
Y
Zhang
Brian P
BP
Gilmour
Hernán A
HA
Navarro
Scott P
SP
Runyon
D002118:Calcium / Q000737:chemistry; D002244:Carbon / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D009479:Neuropeptides / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009584:Nitrogen / Q000737:chemistry; D010100:Oxygen / Q000737:chemistry; D011719:Pyrazines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives
D009479:Neuropeptides; D011719:Pyrazines; C506531:neuropeptide S, human; D002244:Carbon; D014508:Urea; D009584:Nitrogen; D010100:Oxygen; D002118:Calcium