title: Design, parallel synthesis and SAR of novel urotensin II receptor agonists.
abstract: A 30-membered library of amides based on the potent urotensin II (UII) receptor agonist FL104, has been synthesized from ten different carboxylic acids and three amines. A synthetic protocol producing the amides in 47-98% yield has been developed in which the purification involved only extractions and in a few cases filtration through an ion-exchange resin. It was found that 5mg of starting material was enough to obtain reproducible results and excellent purities. Thus, the procedure is estimated to be transferable to fully automated systems. The synthesized compounds were evaluated for their UII receptor agonistic activities using a cell-based assay (R-SAT). The most active compounds were the 4-trifluoromethylcinnamic amides of 1-(4-chlorophenyl)-3-dimethylamino-propylamine and 1-(2-naphthyl)-3-dimethylamino-propylamine, both showed EC(50) values of 130 nM.
authors.affiliation: Department of Chemistry, Medicinal Chemistry, Göteborg University, Kemivagen 10, SE-412 96 Göteborg, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Lehmann
authors.forename: Lisa
authors.initials: L
authors.lastname: Lake
authors.forename: Erika A
authors.initials: EA
authors.lastname: Currier
authors.forename: Roger
authors.initials: R
authors.lastname: Olsson
authors.forename: Uli
authors.initials: U
authors.lastname: Hacksell
authors.forename: Kristina
authors.initials: K
authors.lastname: Luthman
mesh_terms: D000818:Animals; D015195:Drug Design; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D041681:NIH 3T3 Cells; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011437:Propylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: C519260:1-(2-naphthyl)-3-dimethylamino-propylamine; C519261:1-(4-chlorophenyl)-3-dimethylamino-propylamine; D009281:Naphthalenes; D011437:Propylamines; D043562:Receptors, G-Protein-Coupled; C121697:UTS2R protein, human