| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
5-HT6 Receptor
|
|---|---|
| ln Vitro |
Cerlapirdine is a potent 5-HT6 receptor antagonist with an affinity for 5-HT7 and 5-HT2B receptors. Cerlapirdine attenuated scopolamine- and MK-801-induced deficits in the object recognition and contextual fear conditioning tasks. It also attenuated the combined scopolamine and MK-801-induced deficit in the object recognition task. Cerlapirdine was shown to modulate acetylcholine and glutamate in the hippocampus [2].
|
| ln Vivo |
Cerlapirdine (SAM-531, PF-05212365) is a selective, potent, full antagonist of the 5-hydroxytryptamine 6 (5-HT6) receptor. Cerlapirdine and other 5-HT6 receptor antagonists have been in clinical development for the symptomatic treatment of Alzheimer's disease. A human absorption, distribution, metabolism, and excretion study was conducted to gain further understanding of the metabolism and disposition of cerlapirdine. Because of the low amount of radioactivity administered, total (14)C content and metabolic profiles in plasma, urine, and feces were determined using accelerator mass spectrometry (AMS). After a single, oral 5-mg dose of [(14)C]cerlapirdine (177 nCi), recovery of total (14)C was almost complete, with feces being the major route of elimination of the administered dose, whereas urinary excretion played a lesser role. The extent of absorption was estimated to be at least 70%. Metabolite profiling in pooled plasma samples showed that unchanged cerlapirdine was the major drug-related component in circulation, representing 51% of total (14)C exposure in plasma. One metabolite (M1, desmethylcerlapirdine) was detected in plasma, and represented 9% of the total (14)C exposure. In vitro cytochrome P450 reaction phenotyping studies showed that M1 was formed primarily by CYP2C8 and CYP3A4. In pooled urine samples, three major drug-related peaks were detected, corresponding to cerlapirdine-N-oxide (M3), cerlapirdine, and desmethylcerlapirdine. In feces, cerlapirdine was the major (14)C component excreted, followed by desmethylcerlapirdine. The results of this study demonstrate that the use of the AMS technique enables comprehensive quantitative elucidation of the disposition and metabolic profiles of compounds administered at a low radioactive dose [1].
|
| Animal Protocol |
Based on the pharmacological profile, cerlapirdine (0.5 mg, 1.5 mg, 3 mg and 5 mg, QD) was evaluated in an exploratory study as a monotherapy in mild to moderate AD patients for treatment duration of 4 weeks. Although the primary objective was to assess the safety and tolerability, the efficacy was explored using the MMSE, ADAS-Cog, and subtests of the Cambridge Neuropsychological Test Automated Battery (CANTAB). Trends towards improvement favoring the cerlapirdine treatment were observed on the ADAS-Cog scores and CANTAB [2].
Subsequently, cerlapirdine (1.5 mg, 3 mg and 5 mg, QD) was evaluated in a 52-week phase 2 study for its effects on cognition in mild to moderate AD patients. The primary outcome measure was change from baseline in ADAS-Cog scores at week 24. The study was terminated for reasons of futility (NCT00895895). Futility may be attributed to low 5-HT6 receptor occupancy i.e., <30% after multiple 5 mg doses. No safety concerns were noted with cerlapirdine in the clinical studies [2]. [14C]Cerlapirdine (Fig. 1) was prepared under good manufacturing practices conditions. Cerlapirdine and [14C]cerlapirdine were blended before the preparation of the final (capsule) dosage form. Each capsule was hand-filled, weighed, and capped. Each dose was packed in one capsule per subject, with a target dose of 5.44 mg of the hydrochloride salt or approximately 4.96 mg of active moiety (free base). Each dose vial contained approximately 200 nCi (∼7.4 kBq;... The study population consisted of six healthy, male, Caucasian subjects aged 19 to 48 years, with a mean age of 27 years. The subject demographic and baseline characteristics are summarized in Table 1. The excretion of 14C in urine, feces, and total excretion with time is shown in Fig. 2. After a single oral dose of [14C]cerlapirdine, excretion was essentially complete, with mean (± S.D.) total 14C recovery of 98.3% (± 4.7%) (range: 91.0–103%) up to 336 hours after the dose. Feces was the major... [1]. |
| References | |
| Additional Infomation |
Cerlapirdine has been investigated for the treatment of Alzheimer Disease.
Serotonin (5-HT) plays an important role in the regulation of several basic functions of the central and peripheral nervous system. Among the 5-HT receptors, serotonin-6 (5-HT6) receptor has been an area of substantial research. 5-HT6 receptor is a G-protein-coupled receptor mediating its effects through diverse signaling pathways. Exceptional features of the receptors fueling drug discovery efforts include unique localization and specific distribution in the brain regions having a role in learning, memory, mood, and behavior, and the affinity of several clinically used psychotropic agents. Although non-clinical data suggest that both agonist and antagonist may have similar behavioral effects, most of the agents that entered clinical evaluation were antagonists. Schizophrenia was the initial target; more recently, cognitive deficits associated with Alzheimer's disease (AD) or other neurological disorders has been the target for clinically evaluated 5-HT6 receptor antagonists. Several 5-HT6 receptor antagonists (idalopirdine, intepirdine and latrepirdine) showed efficacy in alleviating cognitive deficits associated with AD in the proof-of-concept clinical studies; however, the outcomes of the subsequent phase 3 studies were largely disappointing. The observations from both non-clinical and clinical studies suggest that 5-HT6 receptor antagonists may have a role in the management of neuropsychiatric symptoms in dementia. Masupirdine, a selective 5-HT6 receptor antagonist, reduced agitation/aggression-like behaviors in animal models, and a post hoc analysis of a phase 2 trial suggested potential beneficial effects on agitation/aggression and psychosis in AD. This agent will be assessed in additional trials, and the outcome of the trials will inform the use of 5-HT6 receptor antagonists in the treatment of agitation in dementia of the Alzheimer's type.[2] |
| Molecular Formula |
C22H24CLN3O3S
|
|---|---|
| Molecular Weight |
445.96
|
| Exact Mass |
445.12269
|
| Elemental Analysis |
C, 59.25; H, 5.42; Cl, 7.95; N, 9.42; O, 10.76; S, 7.19
|
| CAS # |
925447-04-7
|
| Related CAS # |
925448-93-7
|
| Appearance |
Typically exists as solids at room temperature
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
5
|
| Rotatable Bond Count |
7
|
| Heavy Atom Count |
30
|
| Complexity |
636
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
Cl.S(C1=CC=CC2C=CC=CC1=2)(C1=C2C=C(C=CC2=NN1)OCCCN(C)C)(=O)=O
|
| InChi Key |
RNGAZJUESDPASQ-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C22H23N3O3S.ClH/c1-25(2)13-6-14-28-17-11-12-20-19(15-17)22(24-23-20)29(26,27)21-10-5-8-16-7-3-4-9-18(16)21;/h3-5,7-12,15H,6,13-14H2,1-2H3,(H,23,24);1H
|
| Chemical Name |
N,N-dimethyl-3-[(3-naphthalen-1-ylsulfonyl-2H-indazol-5-yl)oxy]propan-1-amine;hydrochloride
|
| Synonyms |
SAM-531 hydrochloride; SAM531 HCl; CERLAPIRDINE HYDROCHLORIDE; SAM 531; Cerlapirdine hydrochloride [USAN]; UNII-2VCB4037GE; 2VCB4037GE; Sam-531 hydrochloride; 925447-04-7; Cerlapirdine hydrochloride (USAN); CERLAPIRDINE HYDROCHLORIDE [WHO-DD];; PF-05212365 hydrochloride
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
|
|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2424 mL | 11.2118 mL | 22.4235 mL | |
| 5 mM | 0.4485 mL | 2.2424 mL | 4.4847 mL | |
| 10 mM | 0.2242 mL | 1.1212 mL | 2.2424 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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