Identification of two novel benzo[b]pyrrolo[1,2-d][1,4]oxazin-4-one derivatives acting as GPER antagonists

The G-protein estrogen receptor (GPR30/GPER) is implicated in a number of key cellular processes in both normal and malignant cells. In particular, the function of GPER has been associated with aggressive features of breast cancer. Currently, only a few compounds have been shown to act as GPER agonists or antagonists. On the basis of data obtained by docking simulations carried over the active site of the receptor with known ligands, we have designed a new class of potential antagonists with an aminopyrrolobenzoxazine moiety linked to a variable bulky aromatic nucleus. These compounds were prepared by reaction of newly synthesized 7-amino-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-4-one with suitable chloro-derivatives. In particular, the quinoxaline and the trimethoxybenzoyl analogs, named PBX1 and PBX2 respectively, showed promising properties in preliminary tests on receptor and thus will be in-depth investigated by various in vitro assays.[1] [1] F. Grande, S. Avino, M.F. Santolla, F. Aiello, C. Rosano, A. Garofalo, M. Maggiolini Eur J Med Chem (submitted).