BAY 41-2272 / Bayer - LARVOL DELTA

Aging impairs urethral function in male rats: Increased outlet resistance and oxidative stress. (PubMed, Auton Neurosci) - "Conversely, relaxation to nitric oxide (NO) donors sodium nitroprusside (SNP) and glyceryl trinitrate (GTN) was reduced, while responses to the cGMP analog 8Br-cGMP and the soluble guanylate cyclase (sGC) stimulator BAY 41-2272 were unchanged. NADPH oxidase 2 (NOX2) and xanthine dehydrogenase (XDH) mRNA were upregulated, while hypoxia-inducible factor 1-alpha (HIF1α) remained unchanged. In summary, middle-aged rats show urethral hypercontractility, impaired relaxation, and oxidative stress, without tissue remodeling or ischemia."

Journal • Preclinical • Cardiovascular • CAT • HIF1A • NOS1 • NOS3

Effects of soluble guanylyl cyclase stimulation on muscle oxygenation and exercise capacity in heart failure with mildly reduced ejection fraction. (PubMed, Exp Physiol) - "We tested the hypotheses that the soluble guanylyl cyclase stimulator BAY 41-2272 (BAY41) would increase exercise tolerance, skeletal muscle interstitial pressure of O2 during contractions and NO sensitivity in rats with HFmrEF. After sodium nitroprusside superfusion, BAY41-treated HFmrEF rats had a significantly elevated muscle oxygenation index during steady-state contractions versus vehicle-treated control animals (3104 ± 703 vs. 2365 ± 682 mmHg·s; p = 0.027). These data suggest that stimulation with soluble guanylyl cyclase can improve skeletal muscle oxygenation and increase the exercise capacity in HFmrEF rats, potentially via enhanced vascular smooth muscle NO sensitivity."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure

Expression of soluble guanylate cyclase (sGC) and its ability to form a functional heterodimer are crucial for reviving the NO-sGC signaling in PAH. (PubMed, Free Radic Biol Med) - "Transwell co-culture of HEK cells stably expressing eNOS with PAH PASMCs also restored the sGC heterodimer and its heme-dependent activity with sGC stimulator, BAY 41-2272...Our studies suggest that factors such as globin NO scavenging along with vascular remodeling in PAH can cause hampered vasodilation which in the face of poor NO levels as occurs in PAH are additional impediments for effective vasodilation. However importantly our studies suggests that future therapies can use low doses of NO along with sGC stimulators as a potential drug for PAH subjects."

Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • CDC37 • HSP90AA1 • NOS3 • SGCA

The multidrug resistance protein (MRP) 4 is expressed and functionally active in isolated bladder from pig. (PubMed, Am J Physiol Regul Integr Comp Physiol) - "MK571 administration resulted in a modest relaxation effect of approximately 26% in carbachol-pre-contracted bladders. The relaxation induced by phosphodiesterase inhibitors such as cilostazol, tadalafil, and sildenafil was significantly potentiated in the presence of MK571...Similarly, stimulation with tadalafil + BAY 41-2272 resulted in roughly 8.2-fold and 3.4-fold increases in intracellular and extracellular cGMP concentrations, respectively. The presence of MK571 reduced only the extracellular levels of cGMP. This study reveals the presence and function of MRP4 transporters within the porcine bladder and paves the way for future research exploring the role of this transporter in both underactive and overactive bladder disorders."

Journal • Overactive Bladder

IL-6/gp130 signaling in CD4+ T cells drives the pathogenesis of pulmonary hypertension. (PubMed, Proc Natl Acad Sci U S A) - "Blockade of IL-6 signaling had an additive effect on conventional PAH therapeutics, such as endothelin receptor antagonist (macitentan) and soluble guanylyl cyclase stimulator (BAY41-2272). These findings suggest that IL-6/gp130 signaling in CD4+ cells plays a critical role in the pathogenesis of PAH."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertension • Inflammation • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • CD4 • IL6

Pharmacological Stimulation of Soluble Guanylate Cyclase Counteracts the Profibrotic Activation of Human Conjunctival Fibroblasts. (PubMed, Cells) - "Here, we evaluated the in vitro effects of stimulation of the sGC enzyme with the cell-permeable pyrazolopyridinylpyrimidine compound BAY 41-2272 in modulating the TGFβ1-mediated profibrotic activation of human conjunctival fibroblasts...In addition, pretreatment with the sGC stimulator was capable of significantly dampening TGFβ1-induced acquisition of a contractile phenotype by conjunctival fibroblasts, as well as phosphorylation of Smad3 and release of the proinflammatory cytokines IL-1β and IL-6. Taken together, our findings are the first to demonstrate the effectiveness of pharmacological sGC stimulation in counteracting conjunctival fibroblast-to-myofibroblast transition, thus providing a promising scientific background to further explore the feasibility of sGC stimulators as potential new adjuvant therapeutic compounds to treat conjunctival fibrotic conditions."

Journal • Fibrosis • Glaucoma • Immunology • Inflammation • Ophthalmology • ACTA2 • CDH2 • COL1A1 • COL1A2 • FAP • IL1B • IL6 • MMP2 • SMAD3 • TGFB1 • TIMP1 • TIMP2

Discovery and Optimization of Novel hDHODH Inhibitors for the Treatment of Inflammatory Bowel Disease. (PubMed, J Med Chem) - "Herein, BAY 41-2272 with a 1H-pyrazolo[3,4-b]pyridine scaffold was identified as an hDHODH inhibitor by screening an active compound library containing 5091 molecules. Notably, w2 exerted better therapeutic effects on ulcerative colitis than hDHODH inhibitor vidofludimus and Janus kinase (JAK) inhibitor tofacitinib. Taken together, w2 is a promising hDHODH inhibitor for the treatment of IBD and deserves to be developed as a preclinical candidate."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis

Ameliorating diabetes-associated atherosclerosis and diabetic nephropathy through modulation of soluble guanylate cyclase. (PubMed, Front Cardiovasc Med) - "In this study, we investigated the therapeutic effects of the sGC stimulator BAY 41-2272 (Bay 41) and the sGC activator BAY 60-2770 (Bay 60) on endpoints of atherosclerosis and renal disease as well as inflammation and oxidative stress in diabetic Apolipoprotein E knockout (ApoE-/-) mice...In the kidneys, treatment with Bay 60 significantly lessened urinary albuminuria, mesangial expansion and nitrotyrosine staining under diabetic conditions. In summary, our head-to-head comparator is the first preclinical study to show that a sGC activator is more efficacious than a sGC stimulator for the treatment of diabetes-associated vascular and renal complications."

Journal • Atherosclerosis • Cardiovascular • Diabetes • Diabetic Nephropathy • Dyslipidemia • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus • APOE

Specific dilation pattern in placental circulation and the NO/sGC role in preeclampsia placental vessels. (PubMed, Front Endocrinol (Lausanne)) - "Exogenous NO donors (sodium nitroprusside, SNP) and soluble guanylate cyclase (sGC) activators (Bay41-2272) decreased the baseline of vessel tone in placental circulation in humans, sheep, and rats, but not in other arteries. Lower NO production and decreased NO/sGC could be one of the reasons for preeclampsia. The findings contribute to understanding specific features of placental circulation and provide information about preeclampsia in placental vessels."

Journal • Gynecology • NOS3

Atrophy signaling pathways in respiratory and limb muscles of guinea pigs exposed to chronic cigarette smoke: role of soluble guanylate cyclase stimulation. (PubMed, Am J Physiol Lung Cell Mol Physiol) - "Long-term treatment with the sGC stimulator BAY 41-2272 resulted in a significant reduction in gastrocnemius levels of the aforementioned proteolytic markers, concomitant with a weight recovery and increased cGMP levels. Remarkably, levels of some of the analyzed biomarkers differed between respiratory and limb muscles. In conclusion, targeting sGC might exert beneficial effects on muscle alterations in COPD patients."

Journal • Chronic Obstructive Pulmonary Disease • Fatigue • Immunology • Muscular Atrophy • Pulmonary Disease • Respiratory Diseases • Targeted Protein Degradation • FBXO32

The Soluble Guanylate Cyclase Stimulator BAY 41-2272 Attenuates Transforming Growth Factor β1-Induced Myofibroblast Differentiation of Human Corneal Keratocytes. (PubMed, Int J Mol Sci) - "Finally, BAY 41-2272 significantly counteracted the TGFβ1-induced myofibroblast-like ability of keratocytes to contract collagen gels, reduced phosphorylated Smad3 protein levels, and attenuated gene expression of proinflammatory cytokines. Collectively, our data show for the first time that BAY 41-2272 is effective in counteracting keratocyte-to-myofibroblast transition, thus providing the rationale for the development of sGC stimulators as novel promising modulators of corneal scarring and fibrosis."

Journal • Corneal Abrasion • Fibrosis • Immunology • ACTA2 • CDH2 • COL1A1 • COL1A2 • PDPN • SMAD3 • TGFB1 • VIM

Use of PDE5 inhibitors as a potential treatment for isolated growth hormone deficiency caused by alternate splicing of GH1 gene. (ESPE 2022) - "Inhibitors of phosphodiesterase 5 (PDE5; e.g., Viagra (sildenafil)), which raise cGMP by inhibiting its hydrolysis to GMP, are widely used for the treatment of erectile dysfunction and pulmonary hypertension, and stimulators of soluble guanylyl cyclases (riociguat), which stimulate cGMP synthesis, are used as treatments for pulmonary hypertension and heart failure...Treatment with BAY 41-2272, a cGMP inducer slightly improved the cell morphology in small isoform GH expressing cells...Another PDE5 inhibitor tadalafil also caused a marked improvement in cell morphology caused by the expression of a small GH isoform. Overall, it seems the strategy to regulate the cGMP levels in cells transfected in small GH isoform works and needs further investigation. A detailed analysis of the impact of PDE5 inhibitors on GH expression and secretion will be presented."

Cardiovascular • Congestive Heart Failure • Endocrine Disorders • Erectile Dysfunction • Growth Hormone Deficiency • Heart Failure • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • Targeted Protein Degradation

Novel Drug Therapy to Prevent Bladder Fibrosis in a Pre-Clinical Model of Posterior Urethral Valves (KIDNEY WEEK 2022) - "Treatment with either sGC activator, cinaciguat or sGC stimulator, BAY 41-2272 (10mg/kg) kept both these variables in the same range as sham surgery (p<0.001). Treatment in 1% serum with BAY 41-2272 reduced expression of fibronectin protein by seven-fold and FN1 gene expression by 20%. Conclusion SGC modulation in an in vivo and in vitro model described here demonstrates prognosis-altering potential for this on-market drug in PUV."

Preclinical • Fibrosis • Immunology • Pediatrics • Transplantation • Urology • FN1 • GAPDH

Responses in Blood Pressure and Kidney Function to Soluble Guanylyl Cyclase Stimulation or Activation in Normal and Diabetic Rats. (PubMed, Nephron) - "sGC agonists impact kidney function directly and because they reduce MAP. The direct tendency to increase GFR is most apparent for MAP reductions <10%. The direct effect is otherwise subtle and overridden when MAP declines more. Effects of sGC agonists on tubular reabsorption are dominated by the effects on MAP."

Journal • Preclinical • Cardiovascular • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Mapping of the sGC Stimulator BAY 41-2272 Binding Site on H-NOX Domain and Its Regulation by the Redox State of the Heme. (PubMed, Front Cell Dev Biol) - "We also propose that ODQ can still oxidize the heme in the H-NOX/NO complex and inhibit sGC activity, even though the heme remains associated with H-NOX. These data provide a more-in-depth understanding of the molecular mode of action of sGC stimulators and can lead to an optimized design and development of novel sGC agonists."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Soluble Guanylate Cyclase Stimulators Reverse In Vitro the Effects of Cigarette Smoke Through Normalization of the c-Jun N-Terminal Kinase (JNK) Pathway in Pulmonary Artery Smooth Muscle Cells (ATS 2022) - "Furthermore, treatment with the soluble guanylate cyclase (sGC) stimulator, BAY41-2272, induced the normalization of ≈50% of altered genes, especially those related to the MAPK pathway...Remarkably, in PASMC cultured with CSE and treated with BAY63-2521 (100uM), the expression level of these genes was normalized to controls. By contrast, there was no significant effect of BAY63-2521 on HPAEC.CONCLUSIONS In conclusion, these results highlight the importance of PASMC in the normalization of JNK pathways by sGC stimulators and suggest a prominent role of these cells in the control of pulmonary hypertension and cigarette smoke-induced emphysema."

Preclinical • Chronic Obstructive Pulmonary Disease • Hypertension • Immunology • Inflammation • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • CASP3 • CDKN1A • MAPK8

Soluble Guanylyl Cyclase Stimulator Improves Contracting Skeletal Muscle Oxygen Pressures in Heart Failure Rats. (PubMed, FASEB J) - "During the rest-contraction transient and throughout the contractions steady-state BAY 41-2272 increases PO isin rats with moderate HFrEF. By improving O delivery and relieving the HF-induced O -dependence of V̇O kinetics these findings support the therapeutic potential for sGC stimulators to reduce vasomotor dysfunction and improve exercise tolerance in HFrEF."

Journal • Preclinical • Cardiovascular • Congestive Heart Failure • Heart Failure • Myocardial Infarction

The role of activation of two different sGC binding sites by NO-dependent and NO-independent mechanisms in the regulation of SACs in rat ventricular cardiomyocytes. (PubMed, Physiol Rep) - "NO donor SNAP, α1-subunit of sGC activator BAY41-2272, sGC blocker ODQ, PKG blocker KT5823, PKG activator 8Br-cGMP, and S-nitrosylation blocker ascorbic acid, were employed...8Br-cGMP reduces I by activating PKG and its phosphorylation. These results demonstrate a significant contribution of S-nitrosylation to the regulation of SACs."

Journal • Preclinical • Atrial Fibrillation • Cardiovascular

Acute Kynurenine Exposure of Rat Thoracic Aorta Induces Vascular Dysfunction via Superoxide Anion Production. (PubMed, Biol Pharm Bull) - "These effects were ameliorated by pretreatment with ascorbic acid, an antioxidant, and CH223191, an aryl hydrocarbon receptor (AhR) inhibitor, but not by apocynin, a reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor. In the endothelium-denuded aorta, kyn significantly attenuated the nitric oxide (NO) donor sodium nitroprusside (SNP)-induced vasorelaxation and increased the O production...Kyn had no influence on the vasorelaxant response to BAY 41-2272, a soluble guanylate cyclase stimulator. This suggested that kyn attenuates the NO-mediated vasorelaxation response by promoting O production in thoracic aorta to inactivate NO. O production is likely stimulated in both vascular endothelium and smooth muscle, the former of which may be mediated by AhR activation."

Journal • Preclinical • Cardiovascular • Nephrology • Renal Disease

sGC stimulation lowers elevated blood pressure in a new canine model of resistant hypertension. (PubMed, Hypertens Res) - "BAY 41-2272 was highly efficient as a standalone treatment in resistant hypertension but was also effective in addition to standard-of-care treatment. These data strongly suggest that soluble guanylyl cyclase stimulators might provide an effective pharmacologic therapy for patients with resistant hypertension."

Journal • Preclinical • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertension

[VIRTUAL] Soluble guanylate cyclase stimulators revert in vitro cigarette smoke effects through JNK pathway normalization (ERS 2021) - "Furthermore, treatment with the soluble guanylate cyclase (sGC) stimulator, BAY41-2272, induced the normalization of ≈50% of altered genes, especially those related to the MAPK pathway...The aim of the present study was to evaluate in vitro the effects of CS on JNK pathway in endothelial (HPAEC) and smooth muscle cells (PASMC) of human pulmonary arteries, as well as the effects of the sGC stimulator BAY63-2521...In conclusion, the in vitro results highlight the importance of JUN and FOS as potential therapeutic targets and suggest the use of sGC stimulators as a treatment for emphysema and PH in COPD. Funded by FIS PI16/01147, SEPAR 888/2019."

Preclinical • Chronic Obstructive Pulmonary Disease • Hypertension • Immunology • Inflammation • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • CASP3 • CDKN1A • PI16 • sGC HDA+

Mixed Lineage Kinase 3 mediates PKG1α impact on cardiac function and controls blood pressure through separate mechanisms. (PubMed, JCI Insight) - "MLK3-/- mice displayed hypertension and increased arterial stiffness, though PKG stimulation with sildenafil or the sGC stimulator BAY41-2272 still reduced BP in MLK3-/- mice. MLK3 kinase inhibition with URMC-099 did not affect BP, but induced LV dysfunction in mice...Mechanistically, MLK3 kinase-dependent effects preserve LV function, while MLK3 kinase-independent signaling regulates BP. These findings suggest augmenting MLK3 kinase activity could preserve LV function in HF but avoid hypotension from PKG1α activation."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertension • Hypotension • MAP3K11

Age-associated bladder and urethral coordination impairment and changes in urethral oxidative stress in rats. (PubMed, Life Sci) - "Age-associated ischemic and oxidative stress in the urethra might be correlated with impairment of the NO/sGC system and with coordination of the bladder and urethra."

Journal • Preclinical • Anesthesia • Ataxia • HIF1A • sGC HDA+

Eriodictyol-Amplified 67-kDa Laminin Receptor Signaling Potentiates the Antiallergic Effect of O-Methylated Catechin. (PubMed, J Nat Prod) - "The ASM-specific inhibitor desipramine inhibited EGCG3″Me-induced suppression of degranulation. The soluble guanylate cyclase (sGC) inhibitor NS2028 weakened the potency of EGCG3″Me, and the sGC activator BAY41-2272 suppressed degranulation...Furthermore, oral administration of the lemon-peel-derived eriodyctiol-7-O-glucoside (3) potentiated the suppressive effect of EGCG3″Me-rich "Benifuuki" green tea on the IgE/Ag-induced passive cutaneous anaphylaxis (PCA) reaction in BALB/c mice. These results suggest that EGCG3″Me inhibits IgE/Ag-mediated degranulation by inducing the 67LR/sGC/ASM signaling pathway, and eriodictyol amplifies this signaling."

Journal • sGC HDA+

Calmodulin Regulates Ciliary Beats in the Human Nasal Mucosa Through Adenylate/Guanylate Cyclases and Protein Kinases A/G. (PubMed, Int Arch Allergy Immunol) - "These results confirmed that the regulatory pathway of ciliary beats in the human nasal mucosa involves calmodulin, adenylate/guanylate cyclases, and protein kinases A/G and indicate that adenylate/guanylate cyclases and protein kinases A/G act downstream of calmodulin, but not vice versa, and that these cyclases relay calmodulin signaling."

Journal • Otorhinolaryngology • Respiratory Diseases • Sinusitis