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Stevenson, G I; Huscroft, I; MacLeod, A M; Swain, C J; Cascieri, M A; Chicchi, G G; Graham, M I; Harrison, T; Kelleher, F J; Kurtz, M; Ladduwahetty, T; Merchant, K J; Metzger, J M; MacIntyre, D E; Sadowski, S; Sohal, B; Owens, A P
Journal of medicinal chemistry, 11/1998, Volume: 41, Issue: 23Journal Article
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).
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