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
Department of Medicinal Chemistry, Neuroscience Research Centre, Merck, Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK.
J Med Chem. 1998 Nov 5;41(23):4623-35. doi: 10.1021/jm980376b.
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).
这些实验室之前报道的研究描述了基于4,4-二取代哌啶环系统的一系列新型高亲和力NK1拮抗剂的设计。进一步的构效关系研究现已确定，为了获得高NK1亲和力，苄基醚侧链必须是3,5-二取代且具有高亲脂性，最佳侧链是3,5-双（三氟甲基）苄基醚12（人NK1的IC50 = 0.95 nM）。额外的研究表明，这类NK1拮抗剂对哌啶氮上更广泛的取代基具有耐受性，包括酰基（38）（人NK1的IC50 = 5.3 nM）和磺酰基（39）（人NK1的IC50 = 5.7 nM）衍生物。经过初步药代动力学分析，选择了两种化合物（32和43）用于树脂毒素诱导的血管渗漏模型的体内研究，两者均显示出优异的结果（ID50分别为0.22和0.28 mg/kg）。
