The angiotensin II type 1 receptor (AT1R) has for a long time been a target for drug therapy due to its involvement in the pathogenesis of hypertension. Even though AT1R was for a long time thought to be the only target for its endogenous ligand angiotensin II (Ang II), Ang II is also a ligand for the angiotensin II type 2 receptor (AT2R). This receptor has gained interest as a potential target for therapeutics with two clinical trials being conducted for different indications; the AT2R antagonist EMA401 in phase II trials for treatment of peripheral neuropathic pain and the AT2R agonist C21 entering phase II clinical trials for idiopathic pulmonary fibrosis. The latter, which originates from our laboratory, can be converted by shifting of the methylene imidazole group from the para to the meta position of the phenyl ring to yield C38 which is an AT2R selective antagonist. In our work, we have used this compound as a prototype to yield two new series of compounds, expanding our knowledge of the factors impacting AT2R affinity. The first series explores the effects on affinity, physical and biological parameters by minor alterations of the C38 phenyl ring, while we in the second series investigate the replacement of the benzyl imidazole head group of C38 with bicyclic amides. One compound in this second series showed a five-fold affinity improvement in comparison with C38. Data from the first series of compounds was also used to propose a new model for the binding mode of analogues to C38 using the newly published AT2R crystal structure.

Synthesis and evaluation of a series of analogues to the AT2R prototype antagonist C38

2019 Fall National Meeting

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