4,4-Disubstituted piperidine high-affinity NK₁ antagonists: Structure- activity relationships and in vivo activity

Previously reported studies from these laboratories described the design of a novel series of high-affinity NK₁ antagonists based on the 4,4- disubstituted piperidine ring system. Further structure-activity studies have now established that for high NK₁ affinity the benzyl ether side chain must be 3,5-disubstituted and highly lipophilic, the optimal side chain being the 3,5-bis(trifluoromethyl)benzyl ether, 12 (hNK₁ IC₅₀ = 0.95 nM). Additional studies have shown that this class of NK₁ antagonist tolerates a wider range of substituents on the piperidine nitrogen, including acyl (38) (hNK₁ IC₅₀ = 5.3 nM) and sulfonyl (39) (hNK₁ IC₅₀ = 5.7 nM) derivatives. Following preliminary pharmacokinetic analysis, two compounds (32 and 43) were selected for in vivo study in the resiniferotoxin-induced vascular leakage model, both showing excellent profiles (ID₅₀ = 0.22 and 0.28 mg/kg, respectively).