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  • Title: A novel soluble guanylyl cyclase activator, BR 11257, acts as a non-stabilising partial agonist of sGC.
    Author: Elgert C, Rühle A, Sandner P, Behrends S.
    Journal: Biochem Pharmacol; 2019 May; 163():142-153. PubMed ID: 30753814.
    Abstract:
    The soluble guanylyl cyclase (sGC) plays a key role in NO/cGMP signalling and is widely recognised to be important in different disease pathomechanisms. The discovery of sGC agonists provides a new opportunity to stimulate the NO/cGMP pathway. One class of compounds are the heme-independent sGC activators, which are thought to bind to oxidised or heme-free sGC. This enzyme is preferentially formed under disease situations accompanied by oxidative stress. Accordingly, this binding mode of sGC activators has quite some appeal for the clinical use of sGC activator drugs in diseases with high oxidative stress burden. However, none of the previous sGC activators, most of them dicarboxylic acid derivatives, has passed clinical trials to date, also because of the potent blood pressure lowering effects. In the current study, we investigate the effects of a new monocarboxylic drug BR 11257 in vitro and in vivo. Activity measurements with purified enzyme indicated gentle sGC activation for BR 11257 resembling a partial agonistic behaviour. In thermal shift measurements, we observed an unexpected difference between BR 11257 and the sGC activators from the dicarboxylic acid type. While activators from the dicarboxylic acid type had a highly thermostabilising influence on sGC, this effect was absent with BR 11257. We hypothesize that the key interaction partner for thermostabilisation is the second carboxylic acid in BAY 60-2770 which is missing in BR 11257. The absence of this thermodynamic receptor stabilisation and the partial agonism may be advantageous to overcome limitations of this class of drugs by avoiding excessive hypotension.
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