title: Synthesis of new benzoxazinone derivatives as neuropeptide Y5 antagonists for the treatment of obesity.
abstract: 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.
authors.affiliation: 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
authors.forename: Antoni
authors.initials: A
authors.lastname: Torrens
authors.forename: Josep
authors.initials: J
authors.lastname: Mas
authors.forename: Adriana
authors.initials: A
authors.lastname: Port
authors.forename: José Aurelio
authors.initials: JA
authors.lastname: Castrillo
authors.forename: Olga
authors.initials: O
authors.lastname: Sanfeliu
authors.forename: Xavier
authors.initials: X
authors.lastname: Guitart
authors.forename: Alberto
authors.initials: A
authors.lastname: Dordal
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Romero
authors.forename: M Angeles
authors.initials: MA
authors.lastname: Fisas
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Sánchez
authors.forename: Enrique
authors.initials: E
authors.lastname: Hernández
authors.forename: Pilar
authors.initials: P
authors.lastname: Pérez
authors.forename: Raquel
authors.initials: R
authors.lastname: Pérez
authors.forename: Helmut
authors.initials: H
authors.lastname: Buschmann
mesh_terms: 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
chemical_list: 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