title: Synthesis and biological evaluation of oxadiazole derivatives as inhibitors of soluble guanylyl cyclase.
abstract: Soluble guanylyl cyclase (sGC) is an ubiquitously expressed enzyme that generates the second messenger cGMP and hence, leads to a number of physiological responses including vasodilation, inhibition of platelet aggregation and neurotransmission. Whilst many activating and stimulating modulators of sGC were identified and studied in recent years, only two selective inhibitors are known: ODQ and NS 2028. Furthermore, a synthetic approach to these inhibitors has not been reported yet. Herein, we describe a novel and efficient synthesis of these inhibitors, as well as the preparation of three different classes of NS 2028 analogues. Biological evaluation of this library using rat aortic smooth muscle cells revealed four new compounds with good to moderate sGC inhibitory activity. Our experiments underline the major importance of the oxadiazole ring in ODQ and NS 2028 for the efficiency of this class of inhibitors.
authors.affiliation: Department of Chemistry and Mineralogy, Institute of Organic Chemistry, University of Leipzig, Johannisallee 29, D-04103 Leipzig, Germany.
authors.forename: Margarete
authors.initials: M
authors.lastname: von Wantoch Rekowski
authors.forename: Anastasia
authors.initials: A
authors.lastname: Pyriochou
authors.forename: Nektarios
authors.initials: N
authors.lastname: Papapetropoulos
authors.forename: Anne
authors.initials: A
authors.lastname: Stössel
authors.forename: Andreas
authors.initials: A
authors.lastname: Papapetropoulos
authors.forename: Athanassios
authors.initials: A
authors.lastname: Giannis
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D032390:Myoblasts, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase
chemical_list: D010069:Oxadiazoles; D018160:Receptors, Cytoplasmic and Nuclear; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP