DSR-141562
目录号 : GC60146
DSR-141562是一种新型的，具有口服活性的、可通透血脑屏障的磷酸二酯酶(PDE)抑制剂。DSR-141562对人PDE1B具有优先选择性，IC50为43.9nM，人PDE1A和1C的IC50值分别为97.6nM和431.8nM。DSR-141562用于精神分裂症相关症状及认知障碍的相关研究。
Cas No.:2007975-22-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
DSR-141562 is a novel, orally active, and selective brain-penetrant phosphodiesterase 1 (PDE1) inhibitor. DSR-141562 shows preferential selectivity for human PDE1B with an IC50 of 43.9 nM, and the IC50 values for human PDE1A and 1C are 97.6 and 431.8 nM, respectively. DSR-141562 can be used for the study of positive symptoms, negative symptoms and cognitive impairments associated with schizophrenia[1][2].
DSR-141562 (oral administration; 30 mg/kg; single dose; plasma and brain exposures 0.5, 1, 2, and 3 hours after administration) exhibits good brain uptake, with the brain-to-blood concentration ratio of unbound drug being 0.99 in rats.DSR-141562 (oral administration; 10 mg/kg; single dose; 2 hours) slightly but significantly increases cGMP contents in the frontal cortex and striatum in rat[1].DSR-141562 (oral administration; 30 mg/kg or 100 mg/kg; single dose; 2 hours) causes a significant increase in cGMP concentration in monkey CSF. The plasma concentrations of unbound this compound are above 43.9 nM (IC50s)for PDE1B in vitro (43.9 nM). DSR-141562 causes a significant increase in cGMP concentration in monkey CSF[1].DSR-141562 (oral administration; 3 mg/kg, 10 mg/kg and 30 mg/kg; single dose) significantly reverses methamphetamine-induced locomotor hyperactivity, but has no effect on spontaneouslocomotor activity at 3 and 10 mg/kg[1].DSR-141562 (oral administration; 0.3 mg/kg, 1 mg/kg or 3 mg/kg) significantly reversed the phencyclidine-induced decrease of social interaction time in mice[1]. Animal Model: Male SpragueDawley rats[1]
[1]. Takeshi Enomoto, et al.A Novel Phosphodiesterase 1 Inhibitor DSR-141562 Exhibits Efficacies in Animal Models for Positive, Negative, and Cognitive Symptoms Associated With Schizophrenia. J Pharmacol Exp Ther [2]. Takeshi Enomoto, et al. The Preclinical Profile of DSR-141562: A Novel Phosphodiesterase 1 Inhibitor for the Treatment of Positive Symptoms, Negative Symptoms and Cognitive Impairments Associated with Schizophrenia.Proceedings for The 93rd Annual Meeting of the Japanese Pharmacological Society
| Cas No. | 2007975-22-4 | SDF | |
| Canonical SMILES | O=C1N(C)C(OC[C@H]2CC[C@H](C(F)(F)F)CC2)=NN3C1=CN=C3C4CCOCC4 | ||
| 分子式 | C19H25F3N4O3 | 分子量 | 414.42 |
| 溶解度 | DMSO: 50 mg/mL (120.65 mM) | 储存条件 | Store at -20°C |
| 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。 |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.413 mL | 12.0651 mL | 24.1301 mL |
| 5 mM | 0.4826 mL | 2.413 mL | 4.826 mL |
| 10 mM | 0.2413 mL | 1.2065 mL | 2.413 mL |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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2.
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A Novel Phosphodiesterase 1 Inhibitor DSR-141562 Exhibits Efficacies in Animal Models for Positive, Negative, and Cognitive Symptoms Associated with Schizophrenia
J Pharmacol Exp Ther 2019 Dec;371(3):692-702.PMID:31578257DOI:10.1124/jpet.119.260869
In our drug discovery program, we identified a novel orally available and brain-penetrant phosphodiesterase (PDE) 1 inhibitor, 3-methyl-7-(tetrahydro-2H-pyran-4-yl)-2-{[trans-4-(trifluoromethyl)cyclohexyl]-methoxy}imidazo[5,1-f][1,2,4]triazin-4(3H)-one (DSR-141562). In the present study, we characterized the preclinical profile of DSR-141562. This compound has preferential selectivity for predominantly brain-expressed PDE1B over other PDE1 family members, and high selectivity for the PDE1 family over other PDE families and 65 other tested biologic targets. Oral administration of DSR-141562 at 10 mg/kg slightly elevated the cGMP concentration, and it potently enhanced the increase of cGMP induced by a dopamine D1 receptor agonist in mouse brains. The cGMP level in monkey cerebrospinal fluid was also elevated after treatment with DSR-141562 at 30 and 100 mg/kg and could be used as a translational biomarker. Since PDE1B is believed to regulate dopaminergic and glutamatergic signal transduction, we evaluated the effects of this compound using schizophrenia-related behavioral assays. DSR-141562 at 3-30 mg/kg potently inhibited methamphetamine-induced locomotor hyperactivity in rats, while it had only minimal effects on the spontaneous locomotor activity. Furthermore, DSR-141562 at 1-100 mg/kg did not induce any signs of catalepsy in rats. DSR-141562 at 0.3-3 mg/kg reversed social interaction and novel object recognition deficits induced by repeated treatment with an N-methyl-D-aspartate receptor antagonist, phencyclidine, in mice and rats, respectively. In common marmosets, DSR-141562 at 3 and 30 mg/kg improved the performance in object retrieval with detour tasks. These results suggest that DSR-141562 is a therapeutic candidate for positive, negative, and cognitive symptoms in schizophrenia. SIGNIFICANCE STATEMENT: This is the first paper showing that a phosphodiesterase 1 inhibitor is efficacious in animal models for positive and negative symptoms associated with schizophrenia. Furthermore, we demonstrated that this compound improved cognitive function in the common marmoset, a nonhuman primate.