Selective angiotensin II AT(2) receptor agonists devoid of the imidazole ring system.
A versatile parallel synthetic method to obtain three series of non-cyclic analogues of the first drug-like selective angiotensin II AT(2) receptor agonist (1) has been developed. In analogy with the transformation of losartan to valsartan it was demonstrated that a non-cyclic moiety could be employed as an imidazole replacement to obtain AT(2) selective compounds. In all the three series, AT(2) receptor ligands with affinities in the lower nanomolar range were found. None of the analogues exhibited any affinity for the AT(1) receptor. Four compounds, 17, 22, 39 and 51, were examined in a neurite outgrowth cell assay. All four compounds were found to exert a high agonistic effect as deduced from their capacity to induce neurite elongation in neuronal cells, as does angiotensin II.
Murugaiah
A M S
AM
Department of Medicinal Chemistry, BMC, Uppsala University, PO Box 574, SE-751 23 Uppsala, Sweden.
Wallinder
Chalotta
C
Mahalingam
A K
AK
Wu
Xiongyu
X
Wan
Yiqian
Y
Plouffe
Bianca
B
Botros
Milad
M
Karlén
Anders
A
Hallberg
Mathias
M
Gallo-Payet
Nicole
N
Alterman
Mathias
M
D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000737:chemistry; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D008024:Ligands; D015394:Molecular Structure; D009215:Myometrium / Q000737:chemistry; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine