Discovery and SAR of potent, orally available and brain-penetrable 5,6-dihydro-4H-3-thia-1-aza-benzo[e]azulen- and 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen derivatives as neuropeptide Y Y5 receptor antagonists.
Combination of structural elements from a potent Y5 antagonist (2) with thiazole fragments that exhibit weak Y5 affinities followed by lead optimisation led to the discovery of (5,6-dihydro-4H-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amino and (4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amino derivatives. Both classes of compounds are capable of delivering potent and selective orally and centrally bioavailable NPY Y5 receptor antagonists.
Rueeger
Heinrich
H
Novartis Pharma AG, Novartis Institutes for BioMedical Research Basel, CH-4002 Basel, Switzerland. heinrich.rueeger@pharma.novartis.com
Gerspacher
Marc
M
Buehlmayer
Peter
P
Rigollier
Pascal
P
Yamaguchi
Yasuchika
Y
Schmidlin
Tibur
T
Whitebread
Steven
S
Nuesslein-Hildesheim
Barbara
B
Nick
Hanspeter
H
Cricione
Leoluca
L
D000284:Administration, Oral; D000818:Animals; D052176:Azulenes; D001682:Biological Availability; D001769:Blood; D001812:Blood-Brain Barrier; D003508:Cycloheptanes / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D007031:Hypothalamus; D020128:Inhibitory Concentration 50; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D052176:Azulenes; D003508:Cycloheptanes; D006575:Heterocyclic Compounds, 3-Ring; D006576:Heterocyclic Compounds, 4 or More Rings; D017476:Receptors, Neuropeptide Y; C100568:neuropeptide Y5 receptor; C005525:azulene