Discovery of Lu AA33810: a highly selective and potent NPY5 antagonist with in vivo efficacy in a model of mood disorder.

Abstract

The structure-activity relationship of a series of tricyclic-sulfonamide compounds 11-32 culminating in the discovery of N-[trans-4-(4,5-dihydro-3,6-dithia-1-aza-benzo[e]azulen-2-ylamino)-cyclohexylmethyl]-methanesulfonamide (15, Lu AA33810) is reported. Compound 15 was identified as a selective and high affinity NPY5 antagonist with good oral bioavailability in mice (42%) and rats (92%). Dose dependent inhibition of feeding was observed after i.c.v. injection of the selective NPY5 agonist ([cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]-hPP). In addition, ip administration of Lu AA33810 (10 mg/kg) produced antidepressant-like effects in a rat model of chronic mild stress.

• Authors: Mathivanan Packiarajan, Mohammad R Marzabadi, Mahesh Desai, Yalei Lu, Stewart A Noble, Wai C Wong, Vrej Jubian, Gamini Chandrasena, Toni D Wolinsky, Hualing Zhong, Mary W Walker, Ove Wiborg, Kim Andersen
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 21 Issue 18 Pg. 5436-41 (Sep 15 2011) ISSN: 1464-3405 [Electronic] England
• PMID: 21782428 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Benzothiepins
• N-((4-((4,5-dihydro(1)benzothiepino(5,4-d)thiazol-2-yl)amino)cyclohexyl)methyl)methanesulfonamide
• Receptors, Neuropeptide Y
• Sulfonamides
• neuropeptide Y5 receptor

Topics

• Animals
• Benzothiepins (chemical synthesis, chemistry, pharmacology)
• Biological Availability
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Discovery
• Drug Evaluation, Preclinical
• Mice
• Molecular Structure
• Mood Disorders (drug therapy, metabolism)
• Rats
• Receptors, Neuropeptide Y (antagonists & inhibitors)
• Stereoisomerism
• Structure-Activity Relationship
• Sulfonamides (chemical synthesis, chemistry, pharmacology)