Decahydroisoquinoline derivatives as novel non-peptidic, potent and subtype-selective somatostatin sst(3) receptor antagonists.
Starting from non-peptidic sst(1)-selective somatostatin receptor antagonists, first compounds with mixed sst(1)/sst(3) affinity were identified by directed structural modifications. Systematic optimization of these initial leads afforded novel, enantiomerically pure, highly potent and sst(3)-subtype selective somatostatin antagonists based on a (4S,4aS,8aR)-decahydroisoquinoline-4-carboxylic acid core moiety. These compounds can efficiently be synthesized and show promising PK properties in rodents.
Novartis Institutes for BioMedical Research, Global Discovery Chemistry-Neuroscience, CH-4002 Basel, Switzerland. thomas.troxler@novartis.com
Thomas
T
Troxler
Konstanze
K
Hurth
Karl-Heinrich
KH
Schuh
Philippe
P
Schoeffter
Daniel
D
Langenegger
Albert
A
Enz
Daniel
D
Hoyer
D000818:Animals; D018360:Crystallography, X-Ray; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics; D008968:Molecular Conformation; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C548725:(4-(3,4-difluorophenyl)-piperazine-1-yl)-(2-(3-(6-methoxypyridin- 3-yl)-2-methylpropyl)decahydroisoquinoline-4-yl)methanone; D007546:Isoquinolines; D020033:Protein Isoforms; D017481:Receptors, Somatostatin; D011994:Recombinant Proteins; C039109:isoquinoline