更新于：2024-06-29
Sitokiren
苹果酸司妥吉仑
更新于：2024-06-29
概要
基本信息
非在研机构- |
最高研发阶段申请上市 |
首次获批日期- |
最高研发阶段(中国)申请上市 |
特殊审评特殊审批 (中国) |
结构
分子式C22H32N6O4 |
InChIKeyGRTDDIZIUSADLD-CRAIPNDOSA-N |
CAS号1399849-02-5 |
关联
18
项与 苹果酸司妥吉仑 相关的临床试验SPH3127片治疗轻中度溃疡性结肠炎的有效性、安全性评价以及剂量探索的多中心、随机、双盲、安慰剂平行对照的II期临床研究
A Multicenter, Randomized, Double-blind, Active-controlled, Parallel, Dose-finding Phase 2 Clinical Study to Evaluate the Efficacy and Safety of SPH3127 Tablets in the Treatment of Diabetic Kidney Disease
评价SPH3127片治疗糖尿病肾脏疾病的多中心、随机、双盲、阳性药平行对照的有效性和安全性的剂量探索性II期临床研究
100 项与 苹果酸司妥吉仑 相关的临床结果
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100 项与 苹果酸司妥吉仑 相关的转化医学
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100 项与 苹果酸司妥吉仑 相关的专利（医药）
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4
项与 苹果酸司妥吉仑 相关的文献（医药）2022-08-25Journal of medicinal chemistry1区 · 医学
Discovery of SPH3127: A Novel, Highly Potent, and Orally Active Direct Renin Inhibitor
1区 · 医学
Article
作者: Takedomi, Kei ; Akatsuka, Hidenori ; Kashima, Akiko ; Iijima, Toru ; Togashi, Yuko ; Xia, Guangxin ; Kawaguchi, Takayuki ; Takahashi, Yoichi ; Sugama, Hiroshi ; Ke, Ying ; Yoneda, Hikaru ; Nishio, Masashi ; Hirai, Miki ; Inui, Yosuke ; Xie, Jianshu ; Iijima, Daisuke ; Shen, Jingkang
Renin is the rate-limiting enzyme in the renin-angiotensin-aldosterone system (RAAS) which regulates blood pressure and renal function and hence is an attractive target for the treatment of hypertension and cardiovascular/renal diseases. However, the development of direct renin inhibitors (DRIs) with favorable oral bioavailability has been a longstanding challenge for many years. This problem was thought to be because most of the reported DRIs were peptide-like structures or nonpeptide-like structures with a molecular weight (MW) of > 600. Therefore, we tried to find nonpeptidomimetic DRIs with a MW of < 500 and discovered the promising 2-carbamoyl morpholine derivative 4. In our efforts to improve the pharmacokinetic profile of 4 without a significant increase in the MW, we discovered compound 18 (SPH3127), which demonstrated higher bioavailability and a more potent antihypertensive effect in preclinical models than aliskiren and has completed a phase II clinical trial for essential hypertension.
2021-04-01Clinical therapeutics4区 · 医学
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SPH3127: A Phase I, Randomized, Double-Blind, Placebo-Controlled Trial
4区 · 医学
Article
作者: Xia, Guangxin ; Lin, Yang ; Yang, Kexu ; Zhang, Leduo ; Xu, Ranchi ; Ke, Ying ; Jing, Shan ; Liu, Wenfang
PURPOSE:
To evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of single- and multiple-dose SPH3127 in healthy individuals.
METHODS:
This was a randomized, double-blind, placebo-controlled, Phase I dose-escalation study.
FINDINGS:
SPH3127 exposure, expressed as Cmax, AUC0-t, and AUC0-∞, was proportionally increased with dose for a range of 25-800 mg (single ascending dose [SAD]) and 100-400 mg daily (multiple ascending doses [MADs]). In an SAD, the Cmax values with 25, 50, 100, 200, 400, and 800 mg of SPH3127 were 90.67, 344.50, 523.50, 1239.50, 2445.00, and 5753.33 ng/mL, respectively. The corresponding AUC0-t values were 294.48, 843.62, 1109.33, 2858.56, 6697.50, and 13057.83 h × ng/mL. In MADs, after the first dose of SPH3127, the Cmax values with 100, 200, and 400 mg of SPH3127 were 421.50, 969.00, and 2468.33 ng/mL, respectively. The corresponding AUC0-t values were 1279.28, 2275.77, and 5934.26 h × ng/mL. At steady state, the Cmax values with 100, 200, and 400 mg of SPH3127 were 514.67, 1419.17, and 2513.33 ng/mL, respectively. The corresponding AUC0-24 values were 1638.14, 3096.20, and 7577.70 h × ng/mL. The median Tmax range from 0.33 to 1.0 h and the median t1/2 from 3 to 4 h. In an SAD, when the dose was >100 mg, plasma renin activity inhibition of up to 90% lasted up to 24 h. In MADs, renin activity was continuously inhibited by up to 90% in each group for 24 h after the last administration. Treatment-emergent adverse events (AEs) were reported in 29.2% of individuals receiving the SAD and 33.3% of those receiving MADs. Only mild adverse events occurred.
IMPLICATIONS:
SPH3127 was well tolerated and had robust and sustained suppression of plasma renin activity. CLINICALTRIALS.
GOV IDENTIFIERS:
NCT03128138 (SAD study) and NCT03255993 (MAD study).
2020-02-01European journal of drug metabolism and pharmacokinetics4区 · 医学
The Nonclinical Pharmacokinetics and Prediction of Human Pharmacokinetics of SPH3127, a Novel Direct Renin Inhibitor
4区 · 医学
Article
作者: Chen, Xiaoyan ; Li, Xin ; Xia, Guangxin ; Zhang, Leduo ; Liu, Yanjun ; Mao, Yu ; Gao, Zhiwei
BACKGROUND:
SPH3127 is a novel direct renin inhibitor designed as an oral drug for the regulation of blood pressure and body fluid homeostasis via the renin-angiotensin-aldosterone system (RAAS). This candidate is now being evaluated in a phase I clinical trial in China.
OBJECTIVES:
The purpose of this study is to investigate detailed nonclinical pharmacokinetic data, and to predict human pharmacokinetic parameters.
METHODS:
In vivo pharmacokinetic studies of SPH3127 were performed to investigate the exposure, absorption, clearance, distribution and metabolism after intravenous and oral administration in rats, beagle dogs and cynomolgus monkeys. The cynomolgus monkey pharmacokinetics/pharmacodynamics study was conducted to investigate the effect-concentration relationship of SPH3127. Its human pharmacokinetic properties were predicted employing an allometric scaling approach based on non-clinical species data. In vitro studies were also employed in a cytochrome P450 (CYP) enzyme phenotyping study, an inhibition and induction study, and a Caco-2 cell permeation and metabolites profile analysis.
RESULTS:
After a single intravenous administration of SPH3127 in rats and monkeys, high clearance and volume of distribution and a short terminal elimination half-life were seen for both species. The oral bioavailability of SPH3127 to rats and monkeys was about 11.5-24.5% and 3.3-11.3%, respectively, with the short peak time, Tmax, ranging from 0.25 to 1.3 h. SPH3127 shows low permeability across Caco-2 cell membranes, and as the substrate of p-gp with apparent efflux characteristics. SPH3127 is mainly distributed in the gastrointestine, liver, kidney, pancreas and lung after oral dose in rats, and which decreased quickly to a 1% peak concentration during 12 h. The plasma protein binding ratio of SPH3127 is low as 11.7-14.8% for all species. Excretion studies in rats suggested that fecal, urine and bile excretion represented about 15% of the intake dose, indicating that SPH3127 undergoes extensive metabolism after oral dosing. Phenotyping data revealed that CYP3A4 was the most active enzyme catalyzing the metabolism of SPH3127. The key metabolites were likely N-hydroxylation (M8-7), mono-oxidation-dehydrogenation (M7-4) and mono-oxidation (M8-1, M8-2), both for in vitro liver microsome incubation of all species and in vivo results in rats. The in vitro CYP inhibition study only found very weak action for CYP3A4 (midazolam 1'-hydroxylation) and CYP3A4 (midazolam 6β-hydroxylation) with IC50 of 56.8 µM and 41.1 µM, respectively. Monkey pharmacokinetic/pharmacodynamic data showed favorable safety margins when compared with the exposure of the effect dose and that of the monkey NOAEL level. Simple four-species allometric scaling led to predicted human plasma clearance and volume of distribution, and then simulated the oral human plasma concentration-time profile, which are both in good consistency with phase I clinical trial pharmacokinetic data.
CONCLUSIONS:
SPH 3127 has appropriate pharmacokinetic properties for further clinical exploration.
100 项与 苹果酸司妥吉仑 相关的药物交易
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研发状态
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 高血压 | 申请上市 | 中国 | 2023-06-17 | |
| 原发性高血压 | 临床3期 | 中国 | 2021-05-18 | |
| 原发性高血压 | 临床3期 | 中国 | 2021-05-18 | |
| 糖尿病肾病 | 临床2期 | 中国 | 2023-01-06 | |
| 溃疡性结肠炎 | 临床2期 | 美国 | 2021-08-28 |
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临床结果
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适应症
分期
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临床1期 | - | - | 夢範繭製選範鑰膚憲鏇(鹽繭醖夢憲廠選顧製廠) = 壓壓壓醖夢艱選築憲壓 襯積憲醖觸鑰繭衊淵淵 (構齋網積壓衊獵憲鏇憲 ) | 积极 | 2021-04-01 |
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