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Vitamin B?? derivatives as activators of soluble guanylyl cyclase.

ABSTRACT: Various newly prepared and previously known vitamin B?? derivatives have been studied as potential soluble guanylyl cyclase (sGC) activators. All compounds tested were found to activate the sGC enzyme, although to differing extents. The best results were obtained with the derivatives synthesized from c-lactone and possessing aliphatic amides in the c- and d-positions.

SUBMITTER: o Proinsias K

PROVIDER: S-EPMC3671888 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Vitamin B₁₂ derivatives as activators of soluble guanylyl cyclase.

ó Proinsias Keith K Gryko Daniel T DT Hisaeda Yoshio Y Martin Emil E Sessler Jonathan L JL Gryko Dorota D

Journal of medicinal chemistry 20121005 20

Various newly prepared and previously known vitamin B₁₂ derivatives have been studied as potential soluble guanylyl cyclase (sGC) activators. All compounds tested were found to activate the sGC enzyme, although to differing extents. The best results were obtained with the derivatives synthesized from c-lactone and possessing aliphatic amides in the c- and d-positions. ...[more]

PMID: 22991977

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Project description:Herein, we present the structure-based design, synthesis and biological evaluation of novel mono- and di-carboxylic 3,4-dihydroquinoxalin-2(1H)-one derivatives as potential heme-independent activators of soluble guanylate cyclase (sGC). Docking calculations of several known sGC agonists by utilizing both a homology model of human sGC β1 Η-ΝΟΧ domain and a recent cryo-EM structure of the same domain guided the structural optimization of various designed compounds. Among these, mono- and di-carboxylic 3,4-dihydroquinoxalin-2(1H)-one derivatives arose as promising candidate sGC activators. A series of such compounds was synthesized and assessed for their effect on sGC activity. None of them was able to trigger any detectable activation of native sGC in prostate cancer (LnCaP) or rat aortic smooth muscle (A7r5) cells, even after loss of heme by treatment with the heme oxidant ODQ. Furthermore, selected derivatives did not exhibit any antagonistic effect against the known heme-independent sGC activator BAY 60-2770 nor any additive or synergistic effect with the heme-dependent NO donor sodium nitroprusside (SNP) on heme-associated sGC in A7r5 cells. However, when tested in vitro using purified recombinant sGC enzyme, the dicarboxylic 3,4-dihydroquinoxalin-2(1H)-one derivative 30d was able to increase the enzymatic activity of both the wild-type α1/β1 sGC dimer (by 4.4-fold, EC50 = 0.77 μΜ) as well as the heme-free α1/β1 His105Ala mutant sGC (by 4.8-fold, EC50 = 1.8 μΜ). Notably, the activity of compound 30d towards the mutant α1/β1 Η105A enzyme was comparable with that previously reported by us for the bona fide activator BAY 60-2770, using the functionally equivalent wild-type sGC preparation treated with ODQ. These results indicate that compound 30d can indeed act as a promising sGC activator and may serve as a basic structure in the design of novel, optimized analogues with enhanced sGC agonistic activity and improved efficiency in cell-based and in vivo systems.

Project description:Background and purposeGeneration of cGMP via NO-sensitive soluble guanylyl cyclase (sGC) has been implicated in the regulation of renal functions. Chronic kidney disease (CKD) is associated with decreased NO bioavailability, increased oxidative stress and oxidation of sGC to its haem-free form, apo-sGC. Apo-sGC cannot be activated by NO, resulting in impaired cGMP signalling that is associated with chronic kidney disease progression. We hypothesised that sGC activators, which activate apo-sGC independently of NO, increase renal cGMP production under conditions of oxidative stress, thereby improving renal blood flow (RBF) and kidney function.Experimental approachTwo novel sGC activators, runcaciguat and BAY-543, were tested on murine kidney. We measured cGMP levels in real time in kidney slices of cGMP sensor mice, vasodilation of pre-constricted glomerular arterioles and RBF in isolated perfused kidneys. Experiments were performed at baseline conditions, under L-NAME-induced NO deficiency, and in the presence of oxidative stress induced by ODQ.Key resultsMouse glomeruli showed NO-induced cGMP increases. Under baseline conditions, sGC activator did not alter glomerular cGMP concentration or NO-induced cGMP generation. In the presence of ODQ, NO-induced glomerular cGMP signals were markedly reduced, whereas sGC activator induced strong cGMP increases. L-NAME and ODQ pretreated isolated glomerular arterioles were strongly dilated by sGC activator. sGC activator also increased cGMP and RBF in ODQ-perfused kidneys.Conclusion and implicationsGC activators increase glomerular cGMP, dilate glomerular arterioles and improve RBF under disease-relevant oxidative stress conditions. Therefore, sGC activators represent a promising class of drugs for chronic kidney disease treatment.Linked articlesThis article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc.

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Vitamin B?? derivatives as activators of soluble guanylyl cyclase.

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Vitamin B₁₂ derivatives as activators of soluble guanylyl cyclase.

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