Benzoxazole piperidines as selective and potent somatostatin receptor subtype 5 antagonists.
SAR studies of a recently described SST5R selective benzoxazole piperidine lead series are described with particular focus on the substitution pattern on the benzyl and benzoxazole side-chains. Introduction of a second meta substituent at the benzyl unit significantly lowers residual hH1 activity and insertion of substituents onto the benzoxazole periphery entirely removes remaining h5-HT2B activity. Compounds with single digit nM activity, functional antagonism and favorable physicochemical properties endowed with a good pharmacokinetic profile in rats are described which should become valuable tools for exploring the pharmacological role of the SST5 receptor in vivo.
F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, Medicinal Chemistry, CH-4070 Basel, Switzerland. rainer_e.martin@roche.com
Rainer E
RE
Martin
Peter
P
Mohr
Hans Peter
HP
Maerki
Wolfgang
W
Guba
Christoph
C
Kuratli
Olivier
O
Gavelle
Alfred
A
Binggeli
Stefanie
S
Bendels
Rubén
R
Alvarez-Sánchez
André
A
Alker
Liudmila
L
Polonchuk
Andreas D
AD
Christ
D000818:Animals; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D018360:Crystallography, X-Ray; D008297:Male; D008968:Molecular Conformation; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D001583:Benzoxazoles; D010880:Piperidines; D017481:Receptors, Somatostatin; C094573:somatostatin receptor 5