A5035601241- Nitric Oxide and Endothelin Effects
- Phosphodiesterase function and regulation
- Renin-Angiotensin System Studies
- Hormonal Regulation and Hypertension
- Receptor Mechanisms and Signaling
- Eicosanoids and Hypertension Pharmacology
- Vagus Nerve Stimulation Research
- Genomics and Chromatin Dynamics
- Adenosine and Purinergic Signaling
- Diet and metabolism studies
- DNA and Nucleic Acid Chemistry
- Pharmacogenetics and Drug Metabolism
- Cannabis and Cannabinoid Research
- Complement system in diseases
- Forensic Toxicology and Drug Analysis
- Hemoglobin structure and function
- Metabolism, Diabetes, and Cancer
- Reproductive System and Pregnancy
- Digestive system and related health
- Electrochemical sensors and biosensors
- Hormonal and reproductive studies
- Pancreatic function and diabetes
- Pulmonary Hypertension Research and Treatments
- Adrenal Hormones and Disorders
- Nutrition and Health in Aging
Cyclerion (United States)
2019-2022
Merck & Co., Inc., Rahway, NJ, USA (United States)
2019
University of Kassel
2019
University of Geneva
2019
Swiss National Science Foundation
2019
Ironwood Pharmaceuticals (United States)
2013-2019
London School of Hygiene & Tropical Medicine
2019
Istituti di Ricovero e Cura a Carattere Scientifico
1999
University of Genoa
1987-1988
Soluble guanylate cyclase (sGC), a key signal-transduction enzyme, increases the conversion of guanosine-5′-triphosphate to cGMP upon binding nitric oxide (NO). Endothelial dysfunction and/or reduced NO signaling have been implicated in cardiovascular disease pathogenesis and complications diabetes associated with other states aging. (sGC) stimulators are small-molecule drugs that bind sGC enhance NO-mediated signaling. The pharmacological characterization IW-1973...
Effective treatments for neurodegenerative diseases remain elusive and are critically needed since the burden of these increases across an aging global population. Nitric oxide (NO) is a gasotransmitter that binds to soluble guanylate cyclase (sGC) produce cyclic guanosine monophosphate (cGMP). Impairment this pathway has been demonstrated in diseases. Normalizing deficient NO-cGMP signaling could address multiple pathophysiological features sGC stimulators small molecules synergize with NO,...
Inflammation in the central nervous system (CNS) is observed many neurological disorders. Nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling plays an essential role modulating neuroinflammation. CYR119 a CNS-penetrant sGC stimulator that amplifies endogenous NO-sGC-cGMP signaling. We evaluated target engagement and effects of on markers neuroinflammation vitro mouse microglial cells vivo quinolinic acid (QA)-induced high-fat diet-induced rodent...
In recent years, soluble guanylate cyclase (sGC, EC 4.6.1.2) has emerged as an attractive therapeutic target for treating cardiovascular diseases and associated with fibrosis end-organ failure. Herein, we describe our design synthesis of a series 4-hydroxypyrimidine sGC stimulators starting internally discovered lead. Our efforts have led to the discovery IWP-051, molecule that achieves good alignment potency, stability, selectivity, pharmacodynamic effects while maintaining favorable...
Nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic 3',5' GMP (cGMP) signaling plays a central role in regulation of diverse processes including smooth muscle relaxation, inflammation, and fibrosis. sGC is activated by the short-lived physiologic mediator NO. stimulators are small-molecule compounds that directly bind to enhance NO-mediated cGMP signaling. Olinciguat,...
Amelioration of neuropathic spinal cord injury (SCI) pain is a clinical challenge. Increasing the endocannabinoid anandamide and other fatty acid amides (FAA) by blocking amide hydrolase (FAAH) has been shown to be antinociceptive in number animal models chronic pain. However, an effect FAAH yet demonstrated rat model SCI Four weeks following SCI, rats developed significantly decreased hind paw withdrawal thresholds, indicative below-level cutaneous hypersensitivity. A group were...
Abstract The pharmacokinetics (PK), metabolism, excretion, mass balance, and tissue distribution of [ 14 C]praliciguat were evaluated following oral administration a 3‐mg/kg dose in Sprague‐Dawley rats quantitative whole‐body autoradiography (QWBA) study conducted male Long‐Evans rats. Plasma T max was 1 hour the t 1/2 total plasma radioactivity 23.7 hours. Unchanged praliciguat accounted for 87.4%, minor metabolite ( N ‐dealkylated‐praliciguat) 7.6% through 48 hours (AUC 0‐48 ). Tissues...
Soluble guanylate cyclase (sGC) is an important intracellular receptor that can be activated by sGC stimulators to produce cyclic guanosine monophosphate (cGMP)protein kinase G (PKG) mediated effects. We have identified a novel series of decreased blood pressure (BP) in rats dose‐dependent manner at oral doses between 1‐10 mg/kg. These compounds possess rat pharmacokinetic profile consistent with predicted once daily administration humans. In this study we evaluated IWP‐121 the Dahl...
Abstract Background and Aims The endocannabinoid (eCB) system includes ligands (anandamide 2‐arachidonoyl glycerol, 2‐AG), receptors catabolizing enzymes (fatty acid amide hydrolase, FAAH monoacylglycerol lipase) expressed in both the brain gut. We investigated whether inhibitor, URB597, influenced visceral pain to colorectal distension (CRD) an acute stress‐related model of hypersensitivity induced by selective corticotropin‐releasing factor receptor subtype 1 (CRF ) agonist, cortagine....
Background Soluble guanylate cyclase (sGC) stimulators demonstrate smooth muscle relaxation and vasodilation via the nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) pathway. A novel class of sGC stimulators, pyrazole-pyrimidines, was synthesized with objective creating a potent, once-a-day (QD) oral treatment for cardiovascular diseases. Several compounds from this were identified as potent in vitro (EC50 = 40-287 nM). These evaluated pharmacokinetic (PK) blood pressure...
Background Soluble guanylate cyclase (sGC) is an intracellular receptor that can be activated by nitric oxide (NO) and sGC stimulators to produce cyclic guanosine monophosphate (cGMP), thereby modulating a number of downstream cellular physiological responses including phosphorylation VASP vasodilation. In the Dahl Salt-Sensitive (DSS) rat model hypertension, cGMP production decreased, most likely due reactive oxygen species (ROS) converting NO peroxynitrite, resulting in depleted pools...
Praliciguat is a soluble guanylate cyclase stimulator that elicits hemodynamic, anti-inflammatory, and antifibrotic effects in preclinical models of metabolic dysfunction. We assessed the praliciguat mouse diet-induced obesity (DIO) model housed at thermoneutrality. At 6 weeks old, male C57BL/6N mice were either maintained on low-fat diet (LFD, lean mice) or placed 60% high-fat (HFD, DIO mice). 14 HFD switched to with (6-mg/kg). Day 28 samples collected for biomarker analysis. In second...
Discovery of IWP-051, a novel orally bioavailable soluble guanylate cyclase stimulator with sustained and dose-dependent hemodynamic effects Takashi Nakai, Nicholas R Perl, Rajesh Iyengar, Ara Mermerian, G-Yoon J Im, Thomas W-H Lee, Glen Rennie, James Jia, Paul A Renhowe, Timothy C Barden, E Sheppeck II, Karthik Iyer, Joon Jung, G Todd Milne, Chrissie Segal, Kimberly Long, Joy Miyashiro, Sylvie Bernier, Sarah Jacobson, Jenny Tobin, Courtney Shea, Peter Germano, Yueh-tyng Chien, Daniel Zimmer
Introduction:The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cGMP signaling pathway plays a fundamental role in modulating diverse physiological processes within the central nervous system (CNS) including blood flow, inflammation, neuroprotection, neuronal signaling, and metabolism.sGC stimulators are small-molecule agonists of sGC that synergize with enhance endogenous NO signaling.As such, may provide therapeutic benefits diseases impaired signaling.Many neurodegenerative have...
Soluble guanylate cyclase (sGC) stimulators have the potential to treat a variety of cardiovascular diseases via nitric oxide (NO)‐sGC‐cyclic guanosine monophosphate (cGMP) pathway. Ironwood Pharmaceuticals has synthesized number novel sGC with objective creating once‐a‐day oral anti‐hypertensive. A screening paradigm that evaluated enzyme stimulation, pharmacokinetics (PK), and pharmacodynamics (PD) identified three induce sustained effects after dosing. Potency against was using an in...
Pulmonary arterial hypertension (PAH) results in increased resistance of blood return to the pulmonary vasculature and concomitant hypertrophy right ventricle heart (RHH). Stimulation NO/sGC/cGMP pathway has been shown reduce RHH preclinical models PAH improves clinical outcomes patients with PAH. We therefore hypothesized that prophylactic treatment an sGC stimulator would prevent a model IWP‐427 is potent (HEK EC 50 =167nM), orally bioavailable stimulator. In this study, single...
Background In the vasculature, nitric oxide (NO) binds and activates smooth muscle soluble guanylate cyclase (sGC), leading to increased intracellular cGMP, which triggers relaxation vasodilation. sGC stimulators are a class of small molecule allosteric modulators, stimulate cGMP production independently NO but also act in synergy with NO. Evidence date suggests that may be balanced vasodilators, meaning they elicit vasorelaxation both arterial venous vasculature; however, there have been...