Selective angiotensin II AT2 receptor agonists with reduced CYP 450 inhibition |
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| Authors: | A.K. Mahalingam Yiqian Wan A.M.S. Murugaiah Charlotta Wallinder Xiongyu Wu Bianca Plouffe Milad Botros Fred Nyberg Anders Hallberg Nicole Gallo-Payet Mathias Alterman |
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| Affiliation: | 1. Department of Organic Pharmaceutical Chemistry, BMC, Uppsala University, PO Box 574, SE-751 23 Uppsala, Sweden;2. Service of Endocrinology, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Quebec, Canada J1H 5N4;3. Department of Physiology and Biophysics, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Quebec, Canada J1H 5N4;4. Department of Biological Research on Drug Dependence, BMC, Uppsala University, PO Box 591, SE-751 23 Uppsala, Sweden |
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| Abstract: | Structural alterations to the benzylic position of the first drug-like selective angiotensin II AT2 receptor agonist (1) have been performed, with the emphasis to reduce the CYP 450 inhibitory property of the initial structure. The imidazole moiety, responsible for the CYP 450 inhibitory effect in 1, was replaced with various heterocycles. In addition, the modes of attachment of the heterocycles, that is, carbon versus nitrogen attachment, and introduction of carbonyl functionalities to the benzylic position have been evaluated. In all the three series, AT2 receptor ligands with affinity in the lower nanomolar range were identified. None of the analogues, regardless of the substituents, exhibited any affinity for the AT1 receptor. Compounds with substantially reduced inhibition of the CYP 450 enzymes were obtained. Among them the compound 60 was found to induce neurite elongation in NG 108-15 cells and served as potent AT2 selective agonist. |
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