GPR39-C3 Datasheet | DC8206

Parameter	Value
Chemical Name	N-[3-Chloro-4-[[[2-(methylamino)-6-(2-pyridinyl)-4-pyrimidinyl]amino]methyl]phenyl]methanesulfonamide
CAS No.	1621175-65-2
Synonyms	TC-G 1008;TC-G-1008;GPR39-C3;N-[3-Chloro-4-[[[2-(methylamino)-6-(2-pyridinyl)-4-pyrimidinyl]amino]methyl]phenyl]methanesulfonamide;N-(3-Chloro-4-(((2-(methylamino)-6-(pyridin-2-yl)pyrimidin-4-yl)amino)methyl)phenyl)methanesulfonamide;BCP18836;BDBM50030788;s6759;A16364
Formula	C18H19ClN6O2S
M.Wt	418.9005
SMILES	ClC1C([H])=C(C([H])=C([H])C=1C([H])([H])N([H])C1C([H])=C(C2=C([H])C([H])=C([H])C([H])=N2)N=C(N([H])C([H])([H])[H])N=1)N([H])S(C([H])([H])[H])(=O)=O
Purity	>98%
Storage	2 years -20°C Powder, 2 weeks 4°C in DMSO, 6 months -80°C in DMSO

Biological Activity

TC-G-1008 (GPR39-C3) is a potent and orally available GPR39 agonist with EC50 values of 0.4 and 0.8 nM for rat and human receptors respectively.

In Vitro

TC-G-1008 shows selectivity over a panel of kinases (IC50s>10 μM) and does not exhibit relevant binding affinity for the related ghrelin and neurotensin-1 receptors (IC50s>30 μM)[1]. In HEK293-GPR39 cells, GPR39-C3, which is a positive allosteric modulator, activates cAMP production (downstream of Gs), IP1 accumulation (downstream of Gq), SRF-RE-dependent transcription (downstream of G12/13), and β-arrestin recruitment. GPR39-C3 induces dose- and time-dependent loss of response in cAMP production by second challenge of the compound[2].

In Vivo

Rat and mouse plasma protein binding for TC-G-1008 is measured as 99.3% and 99.1%, respectively. TC-G-1008 is orally bioavailable in mice and robustly induces acute GLP-1 levels. Upon single oral doses of 10, 30, and 100 mg/kg of aqueous suspensions in 0.5% methylcellulose/0.1% Tween 80, TC-G-1008 achieves, between 1 and 1.5 h, maximal exposures of 1.4, 6.1, and 25.3 μM, respectively[1].

Kinase Assay

HEK293-GPR39 cells are plated and cultured in poly-d-lysine-coated, white, 384-well plates (4000 cells/well) in the growth medium overnight at 37°C in the presence of 5% CO2. For pretreatment of the cells with GPR39 ligands (TC-G-1008) or vehicle control (DMSO), the culture medium is removed and the cells are stimulated with GPR39 ligands in assay buffer for the indicated time at 37°C. Then, the compound solution is removed and washed twice with PBS containing 0.1% BSA. For measurement of intracellular cAMP, the cells are stimulated with drugs in stimulation buffer for 30 min at 37°C. The intracellular cAMP level is determined by using HTRF cAMP dynamic 2 kit[2].

Animal Administration

Mice: Mice are given single oral doses of 10, 30, and 100 mg/kg of TC-G-1008[1].

References & source

[1]. Peukert S, et al. Discovery of 2-Pyridylpyrimidines as the First Orally Bioavailable GPR39 Agonists. ACS Med Chem Lett. 2014 Aug 4;5(10):1114-8.

[2]. Shimizu Y, et al. Rho kinase-dependent desensitization of GPR39; a unique mechanism of GPCR downregulation. Biochem Pharmacol. 2017 Sep 15;140:105-114.

DC Chemicals original product information

Published experimental findings depend on the model and assay conditions. They do not guarantee equivalent performance in every application. For laboratory research use only.

GPR39-C3 — Datasheet