Design and synthesis of 3,5-disubstituted benzamide analogues of DNK333 as dual NK1/NK2 receptor probes

Venkat Manoj Swarna, Bradley J. Undem, Vijaya L. Korlipara

Research output: Contribution to journalArticle

Abstract

N-[(R,R)-(E)-(3,4-dichlorobenzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (DNK333, 1b) has been reported to be a potent and balanced dual neurokinin (tachykinin) receptor antagonist. A recent clinical trial using DNK333 has shown that it blocks the NKA-induced bronchoconstriction in patients with asthma. A series of six analogues 3-8 derived from modification of 3,5-bis(trifluoromethyl)benzamide moiety of DNK333 has been synthesized to serve as the dual NK1/NK2 receptor probes. The 3,5-dinitro substituted benzamide compound 3 was found to possess potent and balanced dual NK1/NK2 receptor antagonist activities (pKb = 8.4 for the NK1 receptors, pKb = 7.87 for the NK2 receptors) in the functional assay using guinea pig trachea. Furthermore, SAR analysis suggests that steric, electronic, and lipophilic characteristics of substituents in the benzamide region of DNK333 have a crucial effect on both the NK1 and NK2 receptor antagonist activities.

Original languageEnglish (US)
Pages (from-to)890-894
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume17
Issue number4
DOIs
StatePublished - Feb 15 2007

Keywords

  • Asthma
  • Neurokinin receptor antagonists

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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