Synthesis and biological evaluation of oxadiazole derivatives as inhibitors of soluble guanylyl cyclase.
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.
von Wantoch Rekowski
Margarete
M
Department of Chemistry and Mineralogy, Institute of Organic Chemistry, University of Leipzig, Johannisallee 29, D-04103 Leipzig, Germany.
Pyriochou
Anastasia
A
Papapetropoulos
Nektarios
N
Stössel
Anne
A
Papapetropoulos
Andreas
A
Giannis
Athanassios
A
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
D010069:Oxadiazoles; D018160:Receptors, Cytoplasmic and Nuclear; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP