title: Discovery of small molecules with vasodilating characteristics and adjustable hydrolytic behavior.
abstract: In this contribution the development of a new class of vasodilating compounds obtained by lead structure optimization is described. Three groups of compounds were synthesized and tested for their activity on various smooth muscle preparations of the guinea pig. Beside the lead compound 3a, the most interesting derivative was 1H-imidazole-1-carbothioic acid O-cyclohexyl ester hydrochloride (5b) with a good selective vasodilating potential on aorta and pulmonary artery rings (EC50 14 μM and 24 μM, respectively). Due to the properties of small molecules the hydrolysis behavior of the compounds can be easily adapted hence opening a new route in terms of duration of the agent's effect. With the aid of structure-activity relationship studies, structural motifs influencing the biological activity on isolated smooth muscle cell preparations of the synthesized compounds were proposed. The presented compounds offer good tools in identifying promising molecules as emergency therapy in myocardial infarction.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Gerda
authors.initials: G
authors.lastname: Brunhofer-Bolzer
authors.affiliation: Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Mario
authors.initials: M
authors.lastname: Gabriel
authors.affiliation: Department of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Studenik
authors.affiliation: Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria. Electronic address: thomas.erker@univie.ac.at.
authors.forename: Thomas
authors.initials: T
authors.lastname: Erker
mesh_terms: D000818:Animals; D001011:Aorta / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D006207:Half-Life; D006868:Hydrolysis; D009682:Magnetic Resonance Spectroscopy; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D011651:Pulmonary Artery / Q000502:physiology; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D014665:Vasodilator Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D014665:Vasodilator Agents; D014508:Urea
keywords: Dithiocarbamide derivatives; O-Thiocarbamate/carbamide derivatives; Steric effect; Thiocarbonic acid; Vasodilation