ML-221

ML-221 is an antagonist of the G protein-coupled receptor (GPCR) APJ (IC₅₀ = 4.8 μM).¹ It is selective for APJ over the angiotensin II type 1 (AT₁) receptor (IC₅₀ = >78 μM). ML-221 antagonizes apelin 13-induced activation of APJ in cAMP and β-arrestin recruitment assays (IC₅₀s = 0.7 and 1.75 μM, respectively). It inhibits proliferation and angiogenesis in Mz-ChA-1 cholangiocarcinoma cells when used at concentrations ranging from 5 to 15 μM.² In vivo, ML-221 (150 μg/kg) reduces tumor growth in a Mz-ChA-1 mouse xenograft model. Intrathecal injection of ML-221 (10 μg per animal) reduces mechanical allodynia and heat hyperalgesia induced by chronic constriction injury (CCI) of the sciatic nerve in rats.³ ML-221 also inhibits pathological angiogenesis and enhances normal vessel recovery in retinal ischemic regions in a mouse model of oxygen-induced retinopathy.⁴

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1. Maloney, P.R., Khan, P., Hedrick, M., et al. Discovery of 4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate (ML221) as a functional antagonist of the apelin (APJ) receptor. Bioorg. Med. Chem. Lett. 22(21), 6656-6660 (2012).

2. Hall, C., Ehrlich, L., Venter, J., et al. Inhibition of the apelin/apelin receptor axis decreases cholangiocarcinoma growth. Cancer Lett. 386, 179-188 (2017).

3. Xiong, Q., He, W., Wang, H., et al. Effect of the spinal apelin‑APJ system on the pathogenesis of chronic constriction injury‑induced neuropathic pain in rats. Mol. Med. Rep. 16(2), 1223-1231 (2017).

4. Ishimaru, Y., Shibagaki, F., Yamamuro, A., et al. An apelin receptor antagonist prevents pathological retinal angiogenesis with ischemic retinopathy in mice. Sci. Rep. 7(1), 15062 (2017).