Selective angiotensin II AT(2) receptor agonists with reduced CYP 450 inhibition.
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.
Mahalingam
A K
AK
Department of Organic Pharmaceutical Chemistry, BMC, Uppsala University, Uppsala, Sweden.
Wan
Yiqian
Y
Murugaiah
A M S
AM
Wallinder
Charlotta
C
Wu
Xiongyu
X
Plouffe
Bianca
B
Botros
Milad
M
Nyberg
Fred
F
Hallberg
Anders
A
Gallo-Payet
Nicole
N
Alterman
Mathias
M
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006822:Hybrid Cells; D007093:Imidazoles / Q000737:chemistry; D051379:Mice; D016501:Neurites / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D006571:Heterocyclic Compounds; D007093:Imidazoles; C552778:N-butyloxycarbonyl-3-(4-(2-oxopyrrolidin-1-ylmethyl)phenyl)-5-isobutylthiophene-2-sulfonamide; D044139:Receptor, Angiotensin, Type 2; D013449:Sulfonamides; D013876:Thiophenes; D003577:Cytochrome P-450 Enzyme System