RET Kinase inhibitor 1

Product NameRET Kinase inhibitor 1
CAS1627856-64-7
MFC22H21F4N3O4
MW467.41
EINECS
MOL File1627856-64-7.mol

Chemical Properties

Boiling point	670.1±55.0 °C(Predicted)
Density	1.37±0.1 g/cm3(Predicted)
storage temp.	2-8°C
solubility	DMSO:81.0(Max Conc. mg/mL);173.29(Max Conc. mM) DMSO:PBS (pH 7.2) (1:3):0.25(Max Conc. mg/mL);0.53(Max Conc. mM) Ethanol:15.5(Max Conc. mg/mL);33.16(Max Conc. mM)
form	A crystalline solid
pka	10.30±0.10(Predicted)
color	White to off-white
InChI	1S/C22H21F4N3O4/c1-4-32-16-9-19(30)27-11-14(16)12-5-6-13(15(23)7-12)8-20(31)28-18-10-17(33-29-18)21(2,3)22(24,25)26/h5-7,9-11H,4,8H2,1-3H3,(H,27,30)(H,28,29,31)
InChIKey	IDXKJSSOUXWLDB-UHFFFAOYSA-N
SMILES	FC(F)(F)C(C)(C)c1[o]nc(c1)NC(=O)Cc2c(cc(cc2)c3c[nH][c](cc3OCC)=O)F

Safety Information

WGK Germany	WGK 3
Storage Class	11 - Combustible Solids

Usage And Synthesis

Description

GSK3179106 is an inhibitor of rearranged during transfection (RET) kinase (IC₅₀ = 0.4 nM). It is selective for RET kinase over VEGF receptor 2 (VEGFR2/KDR; IC₅₀ = 109 nM). GSK3179106 reduces the number of abdominal contractions induced by colorectal distension in acetic acid-sensitized rats when administered at a dose of 10 mg/kg twice per day.

Uses

GSK3179106 is an orally active and selective RET kinase inhibitor with IC50s of 0.4 nM, 0.2 nM for human RET and rat RET, respectively. GSK3179106 has the potential for irritable bowel syndrome (IBS) through the attenuation of post-inflammatory and stress-induced visceral hypersensitivity[1].

in vivo

GSK3179106 (3 or 10 mg/kg; orally; for 3.5 days BID) reduces the visceromotor response (VMR) in comparison to rats given an acetic acid enema and dosed with vehicle^[1].

Animal Model:	Seventy male Sprague Dawley rats (225-250 g, ~7-8 weeks old); Fifty male Fischer 344 rats (225-250 g, ~10-12 weeks old); Sprague Dawley female rats^[1]
Dosage:	3 and 10 mg/kg
Administration:	Oral gavage ; administered BID at 8:00 and 16:00 for 3.5 days
Result:	Reduced the visceral motor response. Led to a 34-43% inhibition in VMR to colorectal distension (CRD) at 10 mg/kg.

References

[1] Russell JP, et al. Exploring the Potential of RET Kinase Inhibition for Irritable Bowel Syndrome: A Preclinical Investigation in Rodent Models of Colonic Hypersensitivity. J Pharmacol Exp Ther. 2019 Feb;368(2):299-307. DOI:10.1124/jpet.118.252973
[2] Russell JP, et al. Enteric RET inhibition attenuates gastrointestinal secretion and motility via cholinergic signaling in rat colonic mucosal preparations. Neurogastroenterol Motil. 2019 Apr;31(4):e13479. DOI:10.1111/nmo.13479

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