Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0034063 (pulmonary edema)
 10,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High-throughput screening and subsequent hit optimization identified 1-piperidinylbenzimidazoles, exemplified by compound 1, as TRPV4 inhibitors. Lead optimization identified potent TRPV4 blocker 19, which has good target activity and pharmacokinetic properties. Inhibitor 19 was then profiled in an in vivo rat model, demonstrating its ability to inhibit TRPV4-mediated pulmonary edema.
ACS Med Chem Lett 2013 Feb 14
PMID:Optimization of a Novel Series of TRPV4 Antagonists with In Vivo Activity in a Model of Pulmonary Edema. 2490 Jun 61

The subarachnoid hemorrhage (SAH) is definitely the best descriptive model of the interaction between cardiovascular system and cerebral damage. The underlying mechanism of cardiovascular alterations after SAH is linked to the adrenergic discharge related to aneurysm rupture. Cardiac and pulmonary complications are common after severe brain injury, especially the aneurismal subarachnoid hemorrhage. Acute neurogenic pulmonary edema is not exceptional; it may occur in 20% of cases and commonly follows a severe subarachnoid hemorrhage. Severe myocardial damage with cardiogenic shock may possibly reveal the SAH (3% of cases) and mislead to wrong diagnosis of ACS with dramatic therapeutic consequences. The contribution of CT and cerebral angiography is essential for diagnosis and treatment. Surgical or endovascular treatment depends on location, size and shape of the aneurysm, on patient's age, neurological status and existence of concomitant diseases. We report the case of a 58 years old patient, with a past medical history of diabetes and hypertension, admitted for acute pulmonary edema with cardiogenic shock. This case illustrates an unusual presentation of aneurismal SAH in a patient presenting with an acute coronary syndrome.
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PMID:A case of subarachnoid hemorrhage revealed by an acute coronary syndrome (ACS). 2630 59

Transient Receptor Potential Vanilloid 4 (TRPV4) is a member of the Transient Receptor Potential (TRP) superfamily of cation channels. TRPV4 is expressed in the vascular endothelium in the lung and regulates the integrity of the alveolar septal barrier. Increased pulmonary vascular pressure evokes TRPV4-dependent pulmonary edema, and therefore, inhibition of TRPV4 represents a novel approach for the treatment of pulmonary edema associated with conditions such as congestive heart failure. Herein we report the discovery of an orally active, potent, and selective TRPV4 blocker, 3-(1,4'-bipiperidin-1'-ylmethyl)-7-bromo-N-(1-phenylcyclopropyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxamide (GSK2193874, 28) after addressing an unexpected off-target cardiovascular liability observed from in vivo studies. GSK2193874 is a selective tool for elucidating TRPV4 biology both in vitro and in vivo.
ACS Med Chem Lett 2017 May 11
PMID:Discovery of GSK2193874: An Orally Active, Potent, and Selective Blocker of Transient Receptor Potential Vanilloid 4. 2852 9

GSK2798745, a clinical candidate, was identified as an inhibitor of the transient receptor potential vanilloid 4 (TRPV4) ion channel for the treatment of pulmonary edema associated with congestive heart failure. We discuss the lead optimization of this novel spirocarbamate series and specifically focus on our strategies and solutions for achieving desirable potency, rat pharmacokinetics, and physicochemical properties. We highlight the use of conformational bias to deliver potency and optimization of volume of distribution and unbound clearance to enable desirable in vivo mean residence times.
ACS Med Chem Lett 2019 Aug 08
PMID:Discovery of GSK2798745: A Clinical Candidate for Inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4). 3141 10

In COVID-19, lung manifestations present as a slowly evolving pneumonia with insidious early onset interstitial pulmonary edema that undergoes acute exacerbation in the late stages and microvascular thrombosis. Currently, these manifestations are considered to be only consequences of pulmonary SARS-CoV-2 virus infection. We are proposing a new hypothesis that neurogenic insult may also play a major role in the pathogenesis of these manifestations. SARS-CoV-2 mediated inflammation of the nucleus tractus solitarius (NTS) may play a role in the acute exacerbation of pulmonary edema and microvascular clotting in COVID-19 patients.
ACS Chem Neurosci 2020 07 15
PMID:Pulmonary Edema in COVID19-A Neural Hypothesis. 3261 78