Novel potent and efficacious nonpeptidic urotensin II receptor agonists.
Six different series of nonpeptidic urotensin II receptor agonists have been synthesized and evaluated for their agonistic activity in a cell-based assay (R-SAT). The compounds are ring-opened analogues of the isochromanone-based agonist AC-7954 with different functionalities constituting the linker between the two aromatic ring moieties. Several of the compounds are highly potent and efficacious, with N-[1-(4-chlorophenyl)-3-(dimethylamino)-propyl]-4-phenylbenzamide oxalate (5d) being the most potent. The pure enantiomers of 5d were obtained from the corresponding diastereomeric amides. It was shown by a combination of X-ray crystallography and chemical correlation that the activity resides in the S-enantiomer of 5d (pEC(50) 7.49).
Department of Chemistry, Medicinal Chemistry, and Department of Chemistry, Organic Chemistry, Göteborg University, SE-412 96 Göteborg, Sweden, Acadia Pharmaceuticals AB, Medeon Science Park, SE-205 12 Malmö, Sweden.
Fredrik
F
Lehmann
Anna
A
Pettersen
Erika A
EA
Currier
Vladimir
V
Sherbukhin
Roger
R
Olsson
Uli
U
Hacksell
Kristina
K
Luthman
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D041681:NIH 3T3 Cells; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D001549:Benzamides; D004952:Esters; D004987:Ethers; C509928:N-(1-(4-chlorophenyl)-3-(dimethylamino)propyl)-4-phenylbenzamide; D043562:Receptors, G-Protein-Coupled; D013449:Sulfonamides; C121697:UTS2R protein, human; D014508:Urea