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Literature DB >> 20493713

Selective angiotensin II AT(2) receptor agonists with reduced CYP 450 inhibition.

A K Mahalingam¹, Yiqian Wan, A M S Murugaiah, Charlotta Wallinder, Xiongyu Wu, Bianca Plouffe, Milad Botros, Fred Nyberg, Anders Hallberg, Nicole Gallo-Payet, Mathias Alterman.

Abstract

Structural alterations to the benzylic position of the first drug-like selective angiotensin II AT(2) 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, AT(2) receptor ligands with affinity in the lower nanomolar range were identified. None of the analogues, regardless of the substituents, exhibited any affinity for the AT(1) 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 AT(2) selective agonist. Copyright 2010 Elsevier Ltd. All rights reserved.

Entities: Chemical Gene

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Year: 2010 PMID： 20493713 DOI： 10.1016/j.bmc.2010.03.064

Source DB: PubMed Journal: Bioorg Med Chem ISSN： 0968-0896 Impact factor: 3.641

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Cited

5 in total

Review 1. The Angiotensin AT₂ Receptor: From a Binding Site to a Novel Therapeutic Target.

Authors: U Muscha Steckelings; Robert E Widdop; Edward D Sturrock; Lizelle Lubbe; Tahir Hussain; Elena Kaschina; Thomas Unger; Anders Hallberg; Robert M Carey; Colin Sumners
Journal: Pharmacol Rev Date: 2022-10 Impact factor: 18.923

2. A Series of Analogues to the AT₂R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode.

Authors: Rebecka Isaksson; Jens Lindman; Johan Wannberg; Jessica Sallander; Maria Backlund; Dhaniel Baraldi; Robert Widdop; Mathias Hallberg; Johan Åqvist; Hugo Gutierrez de Teran; Johan Gising; Mats Larhed
Journal: ChemistryOpen Date: 2019-01-24 Impact factor: 2.911

Selective angiotensin II AT(2) receptor agonists with reduced CYP 450 inhibition.

Review 1. The Angiotensin AT₂ Receptor: From a Binding Site to a Novel Therapeutic Target.

2. A Series of Analogues to the AT₂R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode.

3. Discovery and Optimization of Highly Potent and Selective AT₂R Antagonists to Relieve Peripheral Neuropathic Pain.

4. The Angiotensin II Type 2 Receptor in Brain Functions: An Update.

5. N-Aryl Isoleucine Derivatives as Angiotensin II AT2 Receptor Ligands.

Selective angiotensin II AT(2) receptor agonists with reduced CYP 450 inhibition.

Review 1. The Angiotensin AT2 Receptor: From a Binding Site to a Novel Therapeutic Target.

2. A Series of Analogues to the AT2R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode.

3. Discovery and Optimization of Highly Potent and Selective AT2R Antagonists to Relieve Peripheral Neuropathic Pain.

4. The Angiotensin II Type 2 Receptor in Brain Functions: An Update.

5. N-Aryl Isoleucine Derivatives as Angiotensin II AT2 Receptor Ligands.

Review 1. The Angiotensin AT₂ Receptor: From a Binding Site to a Novel Therapeutic Target.

2. A Series of Analogues to the AT₂R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode.

3. Discovery and Optimization of Highly Potent and Selective AT₂R Antagonists to Relieve Peripheral Neuropathic Pain.