Synthesis of new benzoxazinone derivatives as neuropeptide Y5 antagonists for the treatment of obesity.
Screening of our internal chemical collection against the neuropeptide Y5 (NPY Y5) receptor allowed the identification of a benzoxazine derivative 5f as a hit that showed moderate affinity (IC(50) = 300 nM). With the aim of improving the in vitro potency, a series of 2-benzoxazinone derivatives have been synthesized and tested for NPY Y5 activity. Most of the compounds were found to be potent and selective NPY Y5 antagonists having nanomolar binding affinities for the NPY Y5 receptor and showing functional antagonism in the forskolin-induced cyclic AMP test. Prelimminary studies in order to understand the structure-activity relationship were undertaken. Selected compounds were further evaluated for in vivo efficacy, affording the lead compound 2-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)acetamide 5p, which displayed in vivo activity reducing food intake in rodents.
Torrens
Antoni
A
Department of Discovery Chemistry and Discovery Biology, Laboratorios Dr. Esteve, S.A., Av. Mare de Déu de Montserrat 221, 08041 Barcelona, Spain. atorrens@esteve.es
Mas
Josep
J
Port
Adriana
A
Castrillo
José Aurelio
JA
Sanfeliu
Olga
O
Guitart
Xavier
X
Dordal
Alberto
A
Romero
Gonzalo
G
Fisas
M Angeles
MA
Sánchez
Elisabeth
E
Hernández
Enrique
E
Pérez
Pilar
P
Pérez
Raquel
R
Buschmann
Helmut
H
D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D048588:Benzoxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004435:Eating / Q000187:drug effects; D005449:Fluorenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D010078:Oxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D017476:Receptors, Neuropeptide Y / Q000819:agonists / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C500074:2-(4-(8-methyl-2-oxo-4H-benzo(d)(1,3)oxazin-1-yl)piperidin-1-yl)-N-(9-oxo-9H-fluoren-3-yl)acetamide; D019440:Anti-Obesity Agents; D048588:Benzoxazines; D005449:Fluorenes; D010078:Oxazines; D017476:Receptors, Neuropeptide Y; C100568:neuropeptide Y5 receptor; D005576:Colforsin; D000242:Cyclic AMP