Selective angiotensin II AT(2) receptor agonists: Benzamide structure-activity relationships
ABSTRACT In the investigation of the structure-activity relationship of nonpeptide AT(2) receptor agonists, a series of substituted benzamide analogues of the selective nonpeptide AT(2) receptor agonist M024 have been synthesised. In a second series, the biphenyl scaffold was compared to the thienylphenyl scaffold and the impact of the isobutyl substituent and its position on AT(1)/AT(2) receptor selectivity was also investigated. Both series included several compounds with high affinity and selectivity for the AT(2) receptor. Three of the compounds were also proven to function as agonists at the AT(2) receptor, as deduced from a neurite outgrowth assay, conducted in NG108-15 cells.
- SourceAvailable from: Hélène BeaudryBioorganic & Medicinal Chemistry 09/2008; 16(18):8765. DOI:10.1016/j.bmc.2008.08.045 · 2.95 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Inhibitors of the renin angiotensin aldosterone system (RAAS) represent some of the most widely prescribed, successful and well-tolerated therapeutics of recent times and are of proven worth in the management/prevention of cardiovascular disease and diabetic nephropathy. However, as knowledge has grown about the RAAS and its manifold alternate pathways, loci of action and dynamic response to inhibition, so has the clinical debate as how to best use existing therapeutics as well as how best to conceptualise and design RAAS inhibitors of the future. To provide an overview of the several points of therapeutic anti-RAAS intervention, many of which have already been exploited from 'upstream' renin inhibition to 'midstream' ACE inhibition to 'downstream' angiotensin AT1 receptor blockade. A search of patents for RAAS inhibitors recorded in 2008 was conducted along with a relevant literature search. Each intervention has merits and demerits with implications for RAAS 'escape' phenomena, 'dual inhibition' therapy, long-term clinical efficacy and adverse drug reactions. Renin inhibitors offer the most complete RAAS inhibition, but more downstream interventions are likely to recruit supplementary anti-RAAS mediators and receptor signalling pathways. Furthermore, managing hyperkalaemia-stimulated aldosterone escape during combined ACE inhibitor and angiotensin receptor blocker treatment may realise the full clinical potential of dual inhibition therapy.Expert Opinion on Therapeutic Patents 06/2009; 19(6):753-9. DOI:10.1517/13543770903008536 · 3.44 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Three 11C-radiolabelled high-affinity nonpeptide AT2 receptor-selective ligands were synthesized and one of these was evaluated as positron emission tomography (PET) tracer. The labelling reaction was performed via palladium(0)-mediated aminocarbonylation of the aryl iodide substrate using [11C]carbon monoxide as the labelled precursor. As an example, starting with 10.0 GBq [11C]carbon monoxide, 1.10 GBq of the product N-butoxycarbonyl-3-[4-(N-benzyl-[11C]carbamoyl)-phenyl]-5-isobutylthiophene-2-sulphonamide [11C]4d was obtained in 36% decay-corrected radiochemical yield (from [11C]carbon monoxide), 42 min from end of bombardment with a specific activity of 110 GBq·µmol−1. The N-isopropyl-[11C]carbamoyl-analogue [11C]4c (radiochemical purity >95%) was studied employing autoradiography, organ distribution, and small animal PET. In vitro autoradiography showed specific binding in the pancreas and kidney. Organ distribution in six rats revealed a high uptake in the liver, intestine, kidney, and adrenals. Small animal PET showed rapid and reversible uptake in the kidneys followed by accumulation in the urinary bladder suggesting fast renal excretion of the tracer. In addition, high accumulation was also seen in the liver. For future studies, more metabolically stable tracers will need to be developed. To the best of our knowledge, this is the first attempt of the use of PET imaging for the detection of expressed, fully functional AT2 receptors in living subjects. Copyright © 2010 John Wiley & Sons, Ltd.Journal of Labelled Compounds 08/2010; 53(10):616 - 624. DOI:10.1002/jlcr.1793