GSK 962040 - CAS 923565-21-3
Catalog number:
923565-21-3
Category:
Inhibitor
Not Intended for Therapeutic Use. For research use only.
Molecular Formula:
C25H33FN4O
Molecular Weight:
424.55
COA:
Inquire
Targets:
Motilin Receptor
Description:
GSK 962040 is a selective motilin receptor agonist with pEC50 value of 7.9. It is effective as a stimulant of human and rabbit gastrointestinal motility. lt represents a new opportunity as a treatment in diabetic gastroparesis. It is discovered as a therapeutic agent for conditions associated with delayed gastric emptying. It 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. It is found to enhance the EFS-induced cholinergic contraction and cause a small muscle contraction at high concentration in rabbit isolated gastric antrum. It also induces the contraction of human-isolated stomach preparations at 10μM. It had no significant activity at a range of other receptors (including ghrelin), ion channels and enzymes in vitro. It was preferred because its initial IC50 values at CYP3A4 were significantly higher than our preferred threshold of 10 μM. It induced phasic contractions, the duration of which was dose-related. It strongly facilitated cholinergic activity in the antrum, with lower activity in fundus and small intestine only. It was developed by glaxosmithkline and has been in Cilinic Phase 2.
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Purity:
>98%
Appearance:
White to off-white Solid
Synonyms:
GSK-962040;Camicinal;1-[4-(3-fluoroanilino)piperidin-1-yl]-2-[4-[[(3S)-3-methylpiperazin-1-yl]methyl]phenyl]ethanone
Solubility:
10 mM in DMSO
Storage:
-20°C Freezer
MSDS:
Inquire
Application:
GSK 962040 may be used as a treatment in diabetic gastroparesis.
Quality Standard:
In-house standard
Shelf Life:
2 month in rt, long time
Quantity:
Milligrams-Grams
Boiling Point:
610.0±55.0 °C | Condition: Press: 760 Torr
Melting Point:
144 °C
Density:
1.175±0.06 g/cm3 | Condition: Temp: 20 °C Press: 760 Torr
InChIKey:
RZKDEGZIFSJVNA-IBGZPJMESA-N
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
Canonical SMILES:
CC1CN(CCN1)CC2=CC=C(C=C2)CC(=O)N3CCC(CC3)NC4=CC(=CC=C4)F
Current Developer:
GSK 962040 was developed by glaxosmithkline and has been in Cilinic Phase 2.
1.Discovery of N-(3-fluorophenyl)-1-[(4-([(3S)-3-methyl-1-piperazinyl]methyl)phenyl)acetyl]-4-piperidinamine (GSK962040), the first small molecule motilin receptor agonist clinical candidate.
Westaway SM1, Brown SL, Fell SC, Johnson CN, MacPherson DT, Mitchell DJ, Myatt JW, Stanway SJ, Seal JT, Stemp G, Thompson M, Lawless K, McKay F, Muir AI, Barford JM, Cluff C, Mahmood SR, Matthews KL, Mohamed S, Smith B, Stevens AJ, Bolton VJ, Jarvie EM, S J Med Chem. 2009 Feb 26;52(4):1180-9. doi: 10.1021/jm801332q.
N-(3-fluorophenyl)-1-[(4-([(3S)-3-methyl-1-piperazinyl]methyl)phenyl)acetyl]-4-piperidinamine 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.
2.GSK962040: a small molecule motilin receptor agonist which increases gastrointestinal motility in conscious dogs.
Leming S1, Broad J, Cozens SJ, Otterson M, Winchester W, Lee K, Dukes GE, Sanger GJ. Neurogastroenterol Motil. 2011 Oct;23(10):958-e410. doi: 10.1111/j.1365-2982.2011.01770.x. Epub 2011 Sep 5.
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.
3.GSK962040: a small molecule, selective motilin receptor agonist, effective as a stimulant of human and rabbit gastrointestinal motility.
Sanger GJ1, Westaway SM, Barnes AA, Macpherson DT, Muir AI, Jarvie EM, Bolton VN, Cellek S, Näslund E, Hellström PM, Borman RA, Unsworth WP, Matthews KL, Lee K. Neurogastroenterol Motil. 2009 Jun;21(6):657-64, e30-1. doi: 10.1111/j.1365-2982.2008.01270.x.
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.
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