Paltusotine
(Synonyms: CRN00808) 目录号 : GC63137
Paltusotine (CRN00808) is an orally active, nonpeptide selective somatostatin type 2 (SST2) receptor agonist, has the potential for maintaining GH and IGF-1 levels after depot somatostatin receptor ligand therapy.
Cas No.:2172870-89-0
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Paltusotine (CRN00808) is an orally active, nonpeptide selective somatostatin type 2 (SST2) receptor agonist, has the potential for maintaining GH and IGF-1 levels after depot somatostatin receptor ligand therapy.
[1] Luo R, et al. Journal of the Endocrine Society, Volume 5, Issue Supplement_1, April-May 2021, Page A524.
| Cas No. | 2172870-89-0 | SDF | |
| 别名 | CRN00808 | ||
| 分子式 | C27H22F2N4O | 分子量 | 456.49 |
| 溶解度 | DMSO : 10 mg/mL (21.91 mM; ultrasonic and warming and heat to 60°C) | 储存条件 | |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
||
| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 2.1906 mL | 10.9531 mL | 21.9063 mL |
| 5 mM | 0.4381 mL | 2.1906 mL | 4.3813 mL |
| 10 mM | 0.2191 mL | 1.0953 mL | 2.1906 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
The Future of Somatostatin Receptor Ligands in Acromegaly
J Clin Endocrinol Metab 2022 Jan 18;107(2):297-308.PMID:34618894DOI:10.1210/clinem/dgab726.
Currently, the first-generation somatostatin receptor ligands (fg-SRLs), octreotide LAR and lanreotide autogel, are the mainstays of acromegaly treatment and achieve biochemical control in approximately 40% of patients and tumor shrinkage in over 60% of patients. Pasireotide, a second-generation SRL, shows higher efficacy with respect to both biochemical control and tumor shrinkage but has a worse safety profile. In this review, we discuss the future perspectives of currently available SRLs, focusing on the use of biomarkers of response and precision medicine, new formulations of these SRLs and new drugs, which are under development. Precision medicine, which is based on biomarkers of response to treatment, will help guide the decision-making process by allowing physicians to choose the appropriate drug for each patient and improving response rates. New formulations of available SRLs, such as oral, subcutaneous depot, and nasal octreotide, may improve patients' adherence to treatment and quality of life since there will be more options available that better suit each patient. Finally, new drugs, such as Paltusotine, somatropin, ONO-5788, and ONO-ST-468, may improve treatment adherence and present higher efficacy than currently available drugs.
Paltusotine, a novel oral once-daily nonpeptide SST2 receptor agonist, suppresses GH and IGF-1 in healthy volunteers
Pituitary 2022 Apr;25(2):328-339.PMID:35000098DOI:10.1007/s11102-021-01201-z.
Purpose: Evaluate the pharmacodynamics, pharmacokinetics, and safety of Paltusotine, an orally bioavailable, nonpeptide, somatostatin receptor subtype 2 (SST2) agonist being developed for the treatment of acromegaly and neuroendocrine tumors. Methods: A randomized, double-blind, placebo-controlled, single center, single and multiple ascending dose phase 1 study was conducted in healthy male volunteers who received (i) single-dose of oral Paltusotine 1.25, 2.5, 5, 10, and 20 mg (solution); and 40 and 60 mg (capsules) or (ii) multiple-dose oral Paltusotine capsules once daily 5 mg (× 7 days), 10, 20, and 30 mg (× 10 days). Main outcome measures were pharmacodynamics (changes in growth hormone-releasing hormone [GHRH] stimulated growth hormone [GH] and insulin-like growth factor 1 [IGF-1]), pharmacokinetics, safety, and tolerability. Results: Single-dose cohorts: n = 41 active, n = 14 placebo. Multiple-dose cohorts: n = 24 active, n = 12 placebo. Paltusotine was well tolerated, orally bioavailable, associated with increased plasma concentrations to doses up to 40 mg, and was eliminated with a half-life of approximately 30 h. Single-dose Paltusotine 1.25 to 20 mg suppressed GHRH-stimulated GH secretion by 44% to 93% compared to 15% with placebo. Multiple-dose Paltusotine 5 to 30 mg administered once daily for 10 days suppressed IGF-1 by 19% to 37% compared to an increase of 2.4% with placebo. Conclusions: Paltusotine suppresses GH and IGF-1 in a dose-dependent fashion, with a safety profile similar to currently approved SST2 receptor ligands. Paltusotine is a promising once-daily oral nonpeptide SST2 agonist candidate for managing acromegaly and neuroendocrine tumors. Trial registration: NCT03276858, registered September 8, 2017, retrospectively registered.
ACROBAT Edge: Safety and efficacy of switching injected SRLs to oral Paltusotine in patients with acromegaly
J Clin Endocrinol Metab 2022 Nov 10;dgac643.PMID:36353760DOI:10.1210/clinem/dgac643.
Context: Paltusotine is a once-daily, oral, non-peptide small-molecule somatostatin receptor type 2 (SST2) agonist in clinical development for treatment of acromegaly. Objective: To evaluate change in IGF-I levels in patients switched from octreotide LAR or lanreotide depot monotherapy to Paltusotine. Design: Phase 2, open-label, prospective, multicenter, multinational, non-randomized, single-arm exploratory study in which dosage up-titrations were performed in a double-blinded manner. Setting: 26 global sites. Participants: Patients with acromegaly switched to Paltusotine from injected SRL-based therapy. Interventions: Patients received 13-week treatment with once-daily oral Paltusotine (10-40 mg/day). Main outcome measures: Primary endpoint was change from baseline to week 13 in IGF-I for patients who switched from long-acting octreotide or lanreotide monotherapy to Paltusotine (Group 1). All patients underwent a 4-week Paltusotine washout at end of treatment period (weeks 13-17). IGF-I, GH, patient reported outcome, and safety data were collected. Results: Forty-seven patients enrolled. In Group 1 (n = 25), IGF-I and GH showed no significant change between SRL baseline and end of Paltusotine treatment at week 13 (median change in IGF-I = -0.03×upper limit of normal [ULN], P = 0.6285; GH = -0.05 ng/mL, P = 0.6285). IGF-I and GH rose significantly in the 4 weeks after withdrawing Paltusotine (median change in IGF-I = 0.55×ULN, P < 0.0001 [median increase 39%]; GH = 0.72 ng/mL, P < 0.0001 [109.1% increase]). No patients discontinued due to adverse events; no treatment-related serious adverse events were reported. Conclusions: These results suggest once daily, oral Paltusotine is effective in maintaining IGF-I values in patients with acromegaly who switched from injected SRLs. Paltusotine was well tolerated with a safety profile consistent with other SRLs.
Discovery of Paltusotine (CRN00808), a Potent, Selective, and Orally Bioavailable Non-peptide SST2 Agonist
ACS Med Chem Lett 2022 Dec 10;14(1):66-74.PMID:36655128DOI:10.1021/acsmedchemlett.2c00431.
The discovery of a novel 4-(4-aminopiperidinyl)-3,6-diarylquinoline series of potent SST2 agonists is described. This class of molecules exhibit excellent selectivity over SST1, SST3, SST4, and SST5 receptors. The compound 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-hydroxybenzonitrile (22, Paltusotine, formerly known as CRN00808) showed no direct inhibition of major cytochrome P450 enzymes or the hERG ion channel and had sufficient exposure in rats and excellent exposure in dogs upon oral dosing. In pharmacodynamic studies, compound 22 dose-dependently suppressed growth hormone (GH) secretion induced by an exogenous growth-hormone-releasing hormone (GHRH) challenge in both male and female rats following a single oral dose and suppressed IGF-1 levels with repeated oral administration in both rats and dogs. To the best of our knowledge, compound 22 is the first non-peptide SST2 agonist to advance to human clinical trials and is currently in Phase 3 trials in acromegaly patients and a Phase 2 trial in neuroendocrine tumor patients suffering from carcinoid syndrome.
Prospect of acromegaly therapy: molecular mechanism of clinical drugs octreotide and Paltusotine
Nat Commun 2023 Feb 21;14(1):962.PMID:36810324DOI:10.1038/s41467-023-36673-z.
Somatostatin receptor 2 (SSTR2) is highly expressed in neuroendocrine tumors and represents as a therapeutic target. Several peptide analogs mimicking the endogenous ligand somatostatin are available for clinical use, but poor therapeutic effects occur in a subset of patients, which may be correlated with subtype selectivity or cell surface expression. Here, we clarify the signal bias profiles of the first-generation peptide drug octreotide and a new-generation small molecule Paltusotine by evaluating their pharmacological characteristics. We then perform cryo-electron microscopy analysis of SSTR2-Gi complexes to determine how the drugs activate SSTR2 in a selective manner. In this work, we decipher the mechanism of ligand recognition, subtype selectivity and signal bias property of SSTR2 sensing octreotide and Paltusotine, which may aid in designing therapeutic drugs with specific pharmacological profiles against neuroendocrine tumors.