4,4-DISUBSTITUTED PIPERIDINE HIGH-AFFINITY NK1 ANTAGONISTS - STRUCTURE-ACTIVITY-RELATIONSHIPS AND IN-VIVO ACTIVITY

Previously reported studies from these laboratories described the desi gn of a novel series of high-affinity NK1 antagonists based on the 4,4 -disubstituted piperidine ring system. Further structure-activity stud ies have now established that for high NK1 affinity the benzyl ether s ide chain must be 3,5-disubstituted and highly Lipophilic, the optimal side chain being the 3,5-bis(trifluoromethyl)benzyl ether, 12 (kNK(1) 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) (hNK(1) IC50 = 5.3 nM) and sulfonyl (39) (hNK(1) IC50 = 5.7 nM) derivatives. Following preliminary pharmacokin etic analysis, two compounds (32 and 43) were selected for in vivo stu dy in the resiniferotoxin-induced vascular leakage model, both showing excellent profiles (ID50 = 0.22 and 0.28 mg/kg, respectively).