Hale J J, Mills S G, MacCoss M, Finke P E, Cascieri M A, Sadowski S, Ber E, Chicchi G G, Kurtz M, Metzger J, Eiermann G, Tsou N N, Tattersall F D, Rupniak N M, Williams A R, Rycroft W, Hargreaves R, MacIntyre D E
Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA.
J Med Chem. 1998 Nov 5;41(23):4607-14. doi: 10.1021/jm980299k.
Structural modifications requiring novel synthetic chemistry were made to the morpholine acetal human neurokinin-1 (hNK-1) receptor antagonist 4, and this resulted in the discovery of 2-(R)-(1-(R)-3, 5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-ox o-1 ,2,4-triazol-5-yl)methyl morpholine (17). This modified compound is a potent, long-acting hNK-1 receptor antagonist as evidenced by its ability to displace [125I]Substance P from hNK-1 receptors stably expressed in CHO cells (IC50 = 0.09 +/- 0.06 nM) and by the measurement of the rates of association (k1 = 2.8 +/- 1.1 x 10(8) M-1 min-1) and dissociation (k-1 = 0.0054 +/- 0.003 min-1) of 17 from hNK-1 expressed in Sf9 membranes which yields Kd = 19 +/- 12 pM and a t1/2 for receptor occupancy equal to 154 +/- 75 min. Inflammation in the guinea pig induced by a resiniferatoxin challenge (with NK-1 receptor activation mediating the subsequent increase in vascular permeability) is inhibited in a dose-dependent manner by the oral preadmininstration of 17 (IC50 (1 h) = 0.008 mg/kg; IC90 (24 h) = 1.8 mg/kg), indicating that this compound has good oral bioavailbility and peripheral duration of action. Central hNK-1 receptor stimulation is also inhibited by the systemic preadministration of 17 as shown by its ability to block an NK-1 agonist-induced foot tapping response in gerbils (IC50 (4 h) = 0.04 +/- 0.006 mg/kg; IC50 (24 h) = 0.33 +/- 0.017 mg/kg) and by its antiemetic actions in the ferret against cisplatin challenge. The activity of 17 at extended time points in these preclinical animal models sets it apart from earlier morpholine antagonists (such as 4), and the piperidine antagonists 2 and 3 and could prove to be an advantage in the treatment of chronic disorders related to the actions of Substance P. In part on the basis of these data, 17 has been identified as a potential clinical candidate for the treatment of peripheral pain, migraine, chemotherapy-induced emesis, and various psychiatric disorders.
对吗啉缩醛类人神经激肽-1（hNK-1）受体拮抗剂4进行了需要新型合成化学的结构修饰，由此发现了2-(R)-(1-(R)-3,5-双(三氟甲基)苯乙氧基)-3-(S)-(4-氟)苯基-4-(3-氧代-1,2,4-三唑-5-基)甲基吗啉（17）。这种修饰后的化合物是一种强效、长效的hNK-1受体拮抗剂，这一点可通过其从稳定表达于CHO细胞中的hNK-1受体上置换[125I]P物质的能力得到证明（IC50 = 0.09 ± 0.06 nM），也可通过测量17与在Sf9细胞膜中表达的hNK-1的结合速率（k1 = 2.8 ± 1.1 x 10(8) M-1 min-1）和解离速率（k-1 = 0.0054 ± 0.003 min-1）来证明，这得出Kd = 19 ± 12 pM以及受体占据的t1/2等于154 ± 75分钟。在豚鼠中，由树脂毒素激发（其中NK-1受体激活介导随后血管通透性增加）诱导的炎症，通过口服预先给予17呈剂量依赖性受到抑制（IC50（1小时） = 0.008 mg/kg；IC90（24小时） = 1.8 mg/kg），表明该化合物具有良好的口服生物利用度和外周作用持续时间。全身预先给予17也可抑制中枢hNK-1受体刺激，这表现为它能够阻断沙鼠中NK-1激动剂诱导的足部轻拍反应（IC50（4小时） = 0.04 ± 0.006 mg/kg；IC50（24小时） = 0.33 ± 0.017 mg/kg）以及它在雪貂中对顺铂激发的止吐作用。在这些临床前动物模型中，17在延长时间点的活性使其有别于早期的吗啉拮抗剂（如4）以及哌啶拮抗剂2和3，并且可能在治疗与P物质作用相关的慢性疾病方面成为一个优势。部分基于这些数据，17已被确定为治疗外周疼痛、偏头痛、化疗引起的呕吐以及各种精神疾病的潜在临床候选药物。
