AM-0902 _TRP Channel Antagonist - MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEAM-0902Cat. No.: HY-108329CAS No.: 1883711-97-4分式: CHClNO分量: 370.79作靶点: TRP Channel作通路: Membrane Transporter/Ion Channel; Neuronal Signaling储存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性数据体外实验 DMSO : 1

2、50 mg/mL (404.54 mM; Need ultrasonic and warming)Mass Solvent1 mg 5 mg 10 mg Concentration制备储备液1 mM 2.6969 mL 13.4847 mL 26.9694 mL5 mM 0.5394 mL 2.6969 mL 5.3939 mL10 mM 0.2697 mL 1.3485 mL 2.6969 mL请根据产品在不同溶剂中的溶解度，选择合适的溶剂配制储备液，并请注意储备液的保存式和期限。体内实验 请根据您的实验动物和给药式选择适当的溶解案，配制前请先配制澄清的储备液，再依次添加助溶剂(为保证实验结

3、果的可靠性，体内实验的作液，建议您现现配，当天使；澄清的储备液可以根据储存条件，适当保存；以下溶剂前的百分 指该溶剂在您配制终溶液中的体积占)：1. 请依序添加每种溶剂： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (6.74 mM); Clear solution2. 请依序添加每种溶剂： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (6.74 mM); Clear solution3. 请依序添加每种溶剂： 10% DMSO 90% co

4、rn oilSolubility: 2.5 mg/mL (6.74 mM); Clear solution1/3 Master of Small Molecules 您边的抑制剂师www.MedChemEBIOLOGICAL ACTIVITY物活性 AM-0902种有效的选择性瞬时受体电位 A1 (TRPA1) 拮抗剂，作于 rTRPA1 和 hTRPA1 的 IC50 值分别为71 和 131 nM。IC50 & Target IC50: 71 nM (rTRPA1), 131 nM (hTRPA1) 1体外研究 AM-0902 is a potent, selective antagoni

5、st of TRPA1 with IC50s of 71 and 131 nM for rTRPA1 and hTRPA1,respectively. AM-0902 is highly permeable (average Papp=44.5 cm/s in MDCK cells), an unlikely substratefor P-gp (efflux ratio=1.3 in P-gp overexpressing MDCK cells), and demonstrates good solubility (PBS pH7.4: 226 M, SIF: 248 M). AM-0902

6、 shows good selectivity over other TRP channels, as no activity isobserved against human TRPV1 or TRPV4, or rat TRPV1, TRPV3, or TRPM8, at concentrations up to 10 M. AM-0902 inhibits 45Ca2+ flux upon activation of rat TRPA1 with methylglyoxal with an IC50 of 0.019 M1.体内研究 AM-0902 is a potent, select

7、ive antagonist of TRPA1 in vivo. AM-0902 has moderate terminal elimination half-life (t1/2=0.6 h and 2.8 h for rat (0.5 mg/kg, iv), rat (30 mg/kg, oral). A dose-dependent reduction of allylisothiocyanate (AITC)-induced flinching is observed for AM-0902, with a significant reduction in flinchingobser

8、ved postdosing of 10 and 30 mg/kg. The unbound plasma concentrations (Cu) at 1 h for the 1, 3, 10,and 30 mg/kg doses are 0.0510.024 (n=8), 0.190.11 (n=8), 0.580.35 (n=8), and 2.20.40 (n=8) M,covering the in vitro rat TRPA1 45Ca2+ IC50 at 0.72, 2.7, 8.2, and 30.3 fold, respectively. A good exposure-r

9、esponse relationship is observed in this target coverage model. An unbound in vivo IC50 of 0.35 M, whichis in good agreement with the in vitro rat TRPA1 45Ca2+ IC50, and unbound in vivo IC90 of 1.7 M aredetermined. It is noteworthy that at a dose of 30 mg/kg, AM-0902 engages TRPA1 at concentrations

10、thatexceed the in vivo IC90, making it a useful tool for exploration of in vivo models of acute pain 1.PROTOCOLCell Assay 1 MDCK cells are generated and maintained for the TRPA1 calcium flux assays. On the day of assay, culturemedia is removed and cells are incubated for 10 min at room temperature (

11、RT) with 50 L of AM-0902(compound 27) in AM-0902 dilution buffer HBSS containing 1 mM HEPES+0.1 mg/mL BSA at finalconcentrations (2.0 nM to 40 M, 1:3 ratio), followed by another 3 min incubation at RT. The reaction mixtureis aspirated, and cells are washed three times with phosphate buffer saline (P

12、BS) containing 0.1 mg/mLBSA. Radioactivity is measured using a TopCount microplate scintillation counter. The activation of TRPA1 ismeasured by the cellular uptake of radioactive calcium 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Rats 1Adm

13、inistration 1 Rats are dosed orally with either vehicle (2% HPMC/1% Tween-80) or AM-0902 at 1, 3, 10, or 30 mg/kg.After 1 h, one left ventral hind paw is injected with the TRPA1 agonist AITC (0.1%). AM-0902 is also given byan intravenous (IV) injection to rats (0.5 mg/kg) 1.MCE has not independently

14、 confirmed the accuracy of these methods. They are for reference only.2/3 Master of Small Molecules 您边的抑制剂师www.MedChemEREFERENCES1. Schenkel LB, et al. Optimization of a Novel Quinazolinone-Based Series of Transient Receptor Potential A1 (TRPA1)AntagonistsDemonstrating Potent in Vivo Activity. J Med Chem. 2016 Mar 24;59(6)