362665-56-3
基本信息
1-[3-[3-(4-氯苯基)丙氧基]丙基]哌啶
Tirolisant
Tiprolisant
Pitolisant (BF2.649)
Tiprolisant Pitolisant
TIPROLISANT
BF-2649
BF 2.649
3-(4-Chlorophenyl)propyl 3-piperidinopropyl ether
1-[3-[3-(4-Chlorophenyl)propoxy]propyl]piperidine
Piperidine, 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-
物理化學(xué)性質(zhì)
常見問題列表
發(fā)作性睡病(Narcolepsy)是全球公認(rèn)的罕見病,是一種罕見的睡眠/覺醒障礙疾病,通常被認(rèn)為是終身性疾病,臨床上以日間過度嗜睡(excessivedaytimesleepiness,EDS)、猝倒(cataplexy)、入睡前幻覺、睡眠癱瘓和夜間睡眠紊亂為主要特征,對(duì)患者的生活質(zhì)量、工作或?qū)W習(xí)能力、以及身心健康往往造成嚴(yán)重的影響。
替洛利生是全球范圍內(nèi)唯一獲得發(fā)作性睡病適應(yīng)癥,并且同時(shí)被美國(guó)、歐洲和中國(guó)指南推薦的非精神管控類藥物。全球上市多年來(lái),替洛利生以出色的安全性和有效性而受到臨床的廣泛認(rèn)可。替洛利生在中國(guó)的上市意味著結(jié)束了我國(guó)發(fā)作性睡病患者“超說(shuō)明書”和“紅處方”用藥為主的困局,為我國(guó)患者提供安全、有效和便捷的治療新選擇。
Ki: 0.16 nM (H3 receptor)
EC50: 1.5 nM (H3 receptor)
On the stimulation of guanosine 5′-O-(3-[ 35 S]thio)triphosphate binding to this receptor, Pitolisant (BF2.649) behaves as a competitive antagonist with a K i value of 0.16 nM and as an inverse agonist with an EC 50 value of 1.5 nM and an intrinsic activity ~50% higher than that of ciproxifan. Pitolisant displaces [ 125 I]iodoproxyfan binding from mouse brain cortical membranes with an IC 50 value of 26.4±4.5 nM. Taking into account the K d value of the radioligand (161±9 pM), the deduced K i value for Pitolisant is 14±1 nM. Pitolisant displaces [ 125 I]iodoproxyfan binding from membranes of rat glioma C6 cells stably expressing the human H 3 receptor with an IC 50 value of 4.2±0.2 nM. Taking into account the K d value of the radioligand (50±4 pM), the deduced K i value for Pitolisant is 2.7±0.5 nM. Pitolisant progressively reverses this response with a Hill coefficient close to unity and an IC 50 value of 330±68 nM, leading to a K i value of 17±4 nM. Pitolisant elicits a dose-dependent decrease of the basal-specific [ 35 S]GTPγS binding to membranes with a maximal effect corresponding to 75±1% of the basal-specific binding and an EC 50 value of 1.5±0.1 nM.
The administration of Pitolisantat a single dose of 10 mg/kg 30 min before a single dose of Olanzapine (2 mg/kg b.w.) also significantly affects immobility time in the FST. Subsequent administration of the aforementioned drug sequence in mice statistically significantly increases the duration of immobility in comparison to the time determined in the control group in the FST. It decreased locomotor activity as well. In contrast, the results obtained in subchronic treatment after fifteen administrations of both drugs (Pitolisant 10 mg/kg b.w., and after 30 min Olanzapine 2 mg/kg b.w., and again after 4 h Olanzapine 2 mg/kg b.w.) show that the administration of Pitolisant followed by that of Olanzapine equalized the locomotor activity in mice; in comparison to the level of motility in the control group, to which only Pitolisant is administered. More importantly, this combination of drugs significantly reduces immobility time to the level obtained in the control group in the forced swim test in mice [one-way ANOVA; F (3,20) =4.226,P=0.0181]. Rats given Pitolisant (10 mg/kg) during the conditioning phase stayed 502±94 s on the paired texture, a value not statistically different from that of controls, indicating that Pitolisant did not support place preference.