GSK962040Motilin receptor agonist CAS# 923565-21-3 |
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Quality Control & MSDS
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| Cas No. | 923565-21-3 | SDF | Download SDF |
| PubChem ID | 15984937 | Appearance | Powder |
| Formula | C25H33FN4O | M.Wt | 424.55 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | Camicinal | ||
| Solubility | DMSO : 100 mg/mL (235.54 mM; Need ultrasonic) | ||
| Chemical Name | 1-[4-(3-fluoroanilino)piperidin-1-yl]-2-[4-[[(3S)-3-methylpiperazin-1-yl]methyl]phenyl]ethanone | ||
| SMILES | CC1CN(CCN1)CC2=CC=C(C=C2)CC(=O)N3CCC(CC3)NC4=CC(=CC=C4)F | ||
| Standard InChIKey | RZKDEGZIFSJVNA-IBGZPJMESA-N | ||
| Standard InChI | InChI=1S/C25H33FN4O/c1-19-17-29(14-11-27-19)18-21-7-5-20(6-8-21)15-25(31)30-12-9-23(10-13-30)28-24-4-2-3-22(26)16-24/h2-8,16,19,23,27-28H,9-15,17-18H2,1H3/t19-/m0/s1 | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | GSK962040(Camicinal) is a small molecule, selective motilin receptor agonist with pEC50 of 7.9.
IC50 Value: 7.9 (pEC50) [1]
Target: Motilin Receptor
in vitro: GSK962040 had no significant activity at a range of other receptors (including ghrelin), ion channels and enzymes. In rabbit gastric antrum, GSK962040 300 nmol L 1-10 μmol L 1 caused a prolonged facilitation of the amplitude of cholinergically mediated contractions, to a maximum of 248 ± 47% at 3 μmol L 1. The pEC50 values for motilin, erythromycin and GSK962040 were, respectively, 10.4 ± 0.01 (n = 770), 7.3 ± 0.29 (n = 4) and 7.9 ± 0.09 (n = 17) [1]. GSK962040 activated the dog motilin receptor (pEC50 5.79; intrinsic activity 0.72, compared with [Nle13]-motilin) [2]. GSK962040 was preferred because its initial IC50 values at CYP3A4 were significantly higher than our preferred threshold of 10 μM [3].
in vivo: GSK962040 (5 mg free base kg 1) also produced an increase in total faecal weight over the 2-h postdose period (21.2 ± 4.5 g; P < 0.05) [1]. GSK962040 induced phasic contractions, the duration of which was dose-related (48 and 173 min for 3 and 6 mg kg 1), driven by mean plasma concentrations >1.14 μmol L 1. After the effects of GSK962040 faded, migrating motor complex (MMC) activity returned. Migrating motor complex restoration was unaffected by 3 mg kg 1 GSK962040 but at 6 mg kg 1, MMCs returned 253 min after dosing, compared with 101 min after saline (n = 5 each) [2]. he oral bioavailability (Fpo) of GSK962040 was found to be 48 ( 13%. GSK962040 shows a long lasting effect (T1/2 ) 46.9 ( 5.0 min at 3 μM) when compared with the short-lived effect of [Nle13]motilin (T1/2 ) 11.4 ( 1.5 min at 0.3 μM) [3]. GSK962040 strongly facilitated cholinergic activity in the antrum, with lower activity in fundus and small intestine only [4]. References: | |||||
GSK962040 Dilution Calculator
GSK962040 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.3554 mL | 11.7772 mL | 23.5544 mL | 47.1087 mL | 58.8859 mL |
| 5 mM | 0.4711 mL | 2.3554 mL | 4.7109 mL | 9.4217 mL | 11.7772 mL |
| 10 mM | 0.2355 mL | 1.1777 mL | 2.3554 mL | 4.7109 mL | 5.8886 mL |
| 50 mM | 0.0471 mL | 0.2355 mL | 0.4711 mL | 0.9422 mL | 1.1777 mL |
| 100 mM | 0.0236 mL | 0.1178 mL | 0.2355 mL | 0.4711 mL | 0.5889 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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GSK962040 is a first small-molecule agonist of motilin receptor with pEC50 value of 7.9 [1].
GSK962040 is discovered as a therapeutic agent for conditions associated with delayed gastric emptying. In the in vitro assay using recombinant human motilin receptor, GSK962040 shows an excellent inhibition activity against motilin receptor with pEC50 value of 7.9. GSK962040 is highly selective against motilin receptor over the human ghrelin receptor and hERG. It also has no significant activity against other receptors including 5-HT, adrenergic, dopamine, histamine and adenosine receptors. In rabbit isolated gastric antrum, GSK962040 is found to enhance the EFS-induced cholinergic contraction and cause a small muscle contraction at high concentration. GSK962040 also induces the contraction of human-isolated stomach preparations at 10μM [1, 2].
References:
[1] Westaway S M, Brown S L, Fell S C M, et al. Discovery of N-(3-Fluorophenyl)-1-[(4-([(3 S)-3-methyl-1-piperazinyl] methyl) phenyl) acetyl]-4-piperidinamine (GSK962040), the First Small Molecule Motilin Receptor Agonist Clinical Candidate. Journal of medicinal chemistry, 2009, 52(4): 1180-1189.
[2] Sanger G J, Westaway S M, Barnes A A, et al. GSK962040: a small molecule, selective motilin receptor agonist, effective as a stimulant of human and rabbit gastrointestinal motility. Neurogastroenterology & Motility, 2009, 21(6): 657-e31.
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Discovery of N-(3-fluorophenyl)-1-[(4-([(3S)-3-methyl-1-piperazinyl]methyl)phenyl)acetyl]-4-pi peridinamine (GSK962040), the first small molecule motilin receptor agonist clinical candidate.[Pubmed:19191554]
J Med Chem. 2009 Feb 26;52(4):1180-9.
N-(3-fluorophenyl)-1-[(4-([(3S)-3-methyl-1-piperazinyl]methyl)phenyl)acetyl]-4-pi peridinamine 12 (GSK962040) is a novel small molecule motilin receptor agonist. It possesses excellent activity at the recombinant human motilin receptor and also at the native rabbit motilin receptor where its agonist activity results in potentiation of the amplitude of neuronal-mediated contractions of isolated gastric antrum tissue. Compound 12 also possesses highly promising pharmacokinetic profiles in both rat and dog, and these results, in combination with further profiling in human native tissue and an in vivo model of gastrointestinal transit in the rabbit, have led to its selection as a candidate for further development.
GSK962040: a small molecule motilin receptor agonist which increases gastrointestinal motility in conscious dogs.[Pubmed:21895874]
Neurogastroenterol Motil. 2011 Oct;23(10):958-e410.
BACKGROUND: GSK962040, a small molecule motilin receptor agonist, was identified to address the need for a safe, efficacious gastric prokinetic agent. However, as laboratory rodents lack a functional motilin system, studies in vivo have been limited to a single dose, which increased defecation in rabbits. Motilin agonists do not usually increase human colonic motility, so gastric prokinetic activity needs to be demonstrated. METHODS: The effect of intravenous GSK962040 on gastro-duodenal motility was assessed in fasted dogs implanted with strain gauges. Activity was correlated with blood plasma concentrations of GSK962040 (measured by HPLC-MS/MS) and potency of GSK962040 at the dog recombinant receptor [using a Fluorometric Imaging Plate Reader (Molecular Devices, Wokingham, UK) after expression in HEK293 cells]. KEY RESULTS: GSK962040 activated the dog motilin receptor (pEC(50) 5.79; intrinsic activity 0.72, compared with [Nle(13) ]-motilin). In vivo, GSK962040 induced phasic contractions, the duration of which was dose-related (48 and 173 min for 3 and 6 mg kg(-1) ), driven by mean plasma concentrations >1.14 mumol L(-1) . After the effects of GSK962040 faded, migrating motor complex (MMC) activity returned. Migrating motor complex restoration was unaffected by 3 mg kg(-1) GSK962040 but at 6 mg kg(-1) , MMCs returned 253 min after dosing, compared with 101 min after saline (n=5 each). CONCLUSIONS & INFERENCES: The results are consistent with lower potency for agonists at the dog motilin receptor, compared with humans. They also define the doses of GSK962040 which stimulate gastric motility. Correlation of in vivo and in vitro data in the same species, together with plasma concentrations, guides further studies and translation to other species.
GSK962040: a small molecule, selective motilin receptor agonist, effective as a stimulant of human and rabbit gastrointestinal motility.[Pubmed:19374732]
Neurogastroenterol Motil. 2009 Jun;21(6):657-64, e30-1.
There is an urgent clinical need for a safe, efficacious stimulant of gastric emptying; current therapies include erythromycin (an antibiotic with additional properties which preclude chronic use) and metoclopramide (a 5-hydroxytryptamine type 4 receptor agonist and an antagonist at brain D2 receptors, associated with movement disorders). To move away from the complex motilide structure of erythromycin, a small molecule motilin receptor agonist, GSK962040, was identified and characterized. The compound was evaluated using recombinant human receptors, rabbit and human isolated stomach preparations known to respond to motilin and in vivo, by measuring its ability to increase defecation in conscious rabbits. At the human motilin receptor, the pEC50 (the negative logarithm to base 10 of the EC50 value, the concentration of agonist that produces 50% of the maximal response) values for GSK962040 and erythromycin as agonists were, respectively, 7.9 and 7.3; GSK962040 had no significant activity at a range of other receptors (including ghrelin), ion channels and enzymes. In rabbit gastric antrum, GSK962040 300 nmol L(-1)-10 micromol L(-1) caused a prolonged facilitation of the amplitude of cholinergically mediated contractions, to a maximum of 248 +/- 47% at 3 micromol L(-1). In human-isolated stomach, GSK962040 10 micromol L(-1), erythromycin 10 micromol L(-1) and [Nle13]-motilin 100 nmol L(-1), each caused muscle contraction of similar amplitude. In conscious rabbits, intravenous doses of 5 mg kg(-1) GSK962040 or 10 mg kg(-1) erythromycin significantly increased faecal output over a 2-h period. Together, these data show that GSK962040, a non-motilide structure, selectively activates the motilin receptor. Simplification of the structural requirements to activate this receptor greatly facilitates the design of potentially new medicines for gastroparesis.
The effect of camicinal (GSK962040), a motilin agonist, on gastric emptying and glucose absorption in feed-intolerant critically ill patients: a randomized, blinded, placebo-controlled, clinical trial.[Pubmed:27476581]
Crit Care. 2016 Aug 1;20(1):232.
BACKGROUND: The promotility agents currently available to treat gastroparesis and feed intolerance in the critically ill are limited by adverse effects. The aim of this study was to assess the pharmacodynamic effects and pharmacokinetics of single doses of the novel gastric promotility agent motilin agonist camicinal (GSK962040) in critically ill feed-intolerant patients. METHODS: A prospective, randomized, double-blind, parallel-group, placebo-controlled, study was performed in mechanically ventilated feed-intolerant patients [median age 55 (19-84), 73 % male, APACHE II score 18 (5-37) with a gastric residual volume >/=200 mL]. Gastric emptying and glucose absorption were measured both pre- and post-treatment after intragastric administration of 50 mg (n = 15) camicinal and placebo (n = 8) using the (13)C-octanoic acid breath test (BTt1/2), acetaminophen concentrations, and 3-O-methyl glucose concentrations respectively. RESULTS: Following 50 mg enteral camicinal, there was a trend to accelerated gastric emptying [adjusted geometric means: pre-treatment BTt1/2 117 minutes vs. post- treatment 76 minutes; 95 % confidence intervals (CI; 0.39, 1.08) and increased glucose absorption (AUC240min pre-treatment: 28.63 mmol.min/L vs. post-treatment: 71.63 mmol.min/L; 95 % CI (1.68, 3.72)]. When two patients who did not have detectable plasma concentrations of camicinal were excluded from analysis, camicinal accelerated gastric emptying (adjusted geometric means: pre-treatment BTt1/2 121 minutes vs. post-treatment 65 minutes 95 % CI (0.32, 0.91) and increased glucose absorption (AUC240min pre-treatment: 33.04 mmol.min/L vs. post-treatment: 74.59 mmol.min/L; 95 % CI (1.478, 3.449). In those patients receiving placebo gastric emptying was similar pre- and post-treatment. CONCLUSIONS: When absorbed, a single enteral dose of camicinal (50 mg) accelerates gastric emptying and increases glucose absorption in feed-intolerant critically ill patients. TRIAL REGISTRATION: The study protocol was registered with the US NIH clinicaltrials.gov on 23 December 2009 (Identifier NCT01039805 ).
