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

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 (pK_b = 8.4 for the NK₁ receptors, pK_b = 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.