Biochemistry and Pharmacology of Novel Anthranilic Acid Derivatives Activating Heme-Oxidized Soluble Guanylyl Cyclase
Abstract
The heme-enzyme soluble guanylyl cyclase (sGC) is an ubiquitous NO receptor, which mediates NO downstream signaling by the generation of cGMP. We studied the mechanism of action of the anthranilic acid derivatives 5-chloro-2-(5-chloro-thiophene-2-sulfonylamino-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide sodium salt (HMR1766) (proposed international nonproprietary name, ataciguat sodium) and 2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide (S3448) as a new class of sGC agonists. Both compounds activated different sGC preparations (purified from bovine lung, or crude from human corpus cavernosum) in a concentration-dependent and quickly reversible fashion (EC50 = 0.5-10 microM), with mixed-type activation kinetics. Activation of sGC by these compounds was additive to activation by NO donors, but instead of being inhibited, it was potentiated by the heme-iron oxidants 1H-[1,2,4]-oxdiazolo[3,4-a]quinoxalin-1-one (ODQ) and 4H-8-bromo-1,2,4-oxadiazolo(3,4-d) benz(b)(1,4)oxazin-1-one (NS2028), suggesting that the new compounds target the ferric heme sGC isoform. Protoporphyrin IX acted as a competitive activator, and zinc-protoporphyrin IX inhibited activation of heme-oxidized sGC by HMR1766 and S3448, whereas heme depletion of sGC by Tween 20 treatment reduced activation. Both compounds increased cGMP levels in cultured rat aortic smooth muscle cells; induced vasorelaxation of isolated endothelium-denuded rat aorta, porcine coronary arteries, and human corpus cavernosum (EC50 1 to 10 microM); and elicited phosphorylation of the cGMP kinase substrate vasodilator-stimulated phosphoprotein at Ser239. HMR1766 intravenous bolus injection decreased arterial blood pressure in anesthetized pigs. All of these pharmacological responses to the new compounds were enhanced by ODQ and NS2028. Our findings suggest that HMR1766 and S3448 preferentially activate the NO-insensitive heme-oxidized form of sGC, which exists to a variable extent in vascular tissues, and is a pharmacological target for these new vasodilator drugs.
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Generation of superoxide and hydrogen peroxide mediates critical processes such as angiogenesis, hypoxic adaptation, and energy homeostasis.
“Indeed, the generation of superoxide and hydrogen peroxide, among others, has been shown to mediate critical processes such as angiogenesis, hypoxic adaptation, and energy homeostasis (96, 249, 291, 720, 778, 825, 960).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [825]
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- Authors
- Schindler, U., Strobel, H., Schönafinger, K., Linz, W., Löhn, M., Martorana, P. A., Rütten, H., Schindler, P. W., Busch, A. E., Sohn, M., Töpfer, A., Pistorius, A., Jannek, C., & Mülsch, A.
- Affiliations
- Sanofi (Germany) (DE)
- Johannes Gutenberg University Mainz (DE)
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2006-04
- Volume
- 69
- Issue
- 4
- Pages
- 1260-1268
- ISSN
- 0026-895X (ISSN-L)
- OpenAlex
- W2161776017
- Cited by
- 100
- References
- 28
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 3 · 2022: 1 · 2021: 6 · 2020: 3 · 2019: 2 · 2018: 5 · 2017: 3 · 2016: 3 · 2015: 7 · 2014: 5 · 2013: 11 · 2012: 6
- FWCI
- 3.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- soluble guanylate cyclase, anthranilic acid derivatives, cGMP signaling, protoporphyrin IX, zinc protoporphyrin, vasorelaxation, VASP, arterial blood pressure, pulmonary arterial hypertension, corpus cavernosum, aortic smooth muscle cells, ODQ
- MeSH terms
- Animals, Blood Pressure, Cattle, Enzyme Activation, Guanylate Cyclase, Heme, Oxidation-Reduction, Sulfonamides, Vasodilator Agents, Cyclic GMP-Dependent Protein Kinases, ortho-Aminobenzoates
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