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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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Torrens A,Mas J,Port A,Castrillo JA,Sanfeliu O,Guitart X,Dordal A,Romero G,Fisas MA,Sánchez E,Hernández E,Pérez P,Pérez R,Buschmann H

doi

10.1021/jm049599u

keywords:

subject

Has Abstract

pub_date

2005-03-24 00:00:00

pages

2080-92

issue

6

eissn

0022-2623

issn

1520-4804

journal_volume

48

pub_type

杂志文章

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