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  • As comparators compounds and were made

    2021-10-03

    As comparators, compounds and were made using the pyrazolopyridine core with the CF triazole attached. The 2-fluorophenyl group was replaced with the methylpyrimidine in compound . The potency of these compounds were very good and compound looks attractive from a physicochemical perspective as it had good HLM stability, good solubility with no CYP1A2 activity. As compound had an attractive profile in terms of potency in rat imidazole receptor and good solubility, it was investigated further. It was found to be selective (all IC values >10μM) in wide-ligand profiling over a range of >70 targets including PDE’s (CEREP, Bioprint™, and Dundee Kinase). The pharmacokinetics of and were also determined in rat (). Compound was progressed to in vivo studies and shown to be efficacious in the conscious SHR model of hypertension. In summary, optimization of a series of triazole containing sGC stimulators is described. A combination of the acidic CF triazole group coupled with a pyrimidine gave compounds having sGC activity with a good pharmacokinetic profile. Acknowledgments
    Introduction Soluble guanylate cyclase (sGC) catalyzes the conversion of guanosine triphosphate to cyclic guanosine monophosphate (cGMP) and pyrophosphate. Mammalian sGC is a heterodimeric hemoprotein consisting of a larger α-subunit and a smaller heme-binding β-subunit [1]. The β-subunit binds a stoichiometric amount of heme via a weak interaction between the axial ligand histidine-105 and the anchoring residues of the heme propionates tyrosine-135, serine-137 and arginine-139 (the heme-binding motif Y-x-S-x-R) building a penta-coordinated histidyl-heme complex [2], [3]. Binding of nitric oxide (NO), its primary activator, to the ferrous prosthetic group cleaves the weak Fe2+-proximal His bond, and forms a five-coordinated histidine–heme–NO intermediate that markedly stimulates the enzymatic production of cGMP [4]. The enzyme-heme also binds carbon monoxide (CO) with moderate stimulation of enzyme activity. Many studies are focused on elucidating the molecular mechanism of sGC activation and deactivation with a goal of therapeutic intervention in diseases involving the NO-cGMP pathway including cardiovascular diseases. Concerning sGC activation several heme-dependent stimulators and heme–independent activators have been described [5], [6]. Nevertheless little is known about the deactivation of the enzyme. Apparently, the rate of NO dissociation from the heme moiety plays an essential role in the deactivation of the enzyme in biological systems [7]. It is known that sGC becomes slowly deactivated in air and rapidly deactivated by different redox agents such as ferricyanide and methylene blue. The mechanism of deactivation of sGC by dioxygen in the air is in principle straightforward: heme is oxidized to Fe(III)-heme and nitrate is formed, but the mechanism of deactivation by methylene blue and ferricyanide remains undetermined [8]. Recent studies suggest that oxidative damage can block the non-heme NO binding site, consequently inhibiting NO stimulation of sGC in vivo, providing a mechanistic explanation [9] for sGC inhibition by thiol modifying reagents and oxidants [10], [11]. In the present work, we investigated the possibility of electrochemical monitoring the sGC activation/deactivation by a probe molecule (L1). Accordingly, the effect of the canthin-6-one (L1) on sGC was followed by electro- and bio-chemical methods. Ultimately, the proposed methodology would provide information potentially interesting for medicinal chemistry research concerning sGC. Canthin-6-one (L1) is a natural β-carboline alkaloid, isolated from Zanthoxylum chiloperone (Rutaceae), that possesses an additional D-ring, displaying a characteristic tetracyclic core with a particular naphthyridone motif (See Fig. 1). Although its sGC activity is relatively weak, its electroactive character makes this compound particularly useful as a redox probe. Importantly, several alkaloids of this family display promising biological activities [12], [13].