Author: Thomas, Howard ; Wand, Matthew ; Beasley, David W C ; Carroll, Miles W ; Dejnirattisai, Wanwissa ; Karayiannis, Peter ; Tree, Julia A ; Sadiq, Fouzia ; Mongkolsapaya, Juthathip ; Thursz, Mark ; Screaton, Gavin ; Matthews, Ian ; Elmore, Michael J

The 2',5'- oligoadenylate synthetase (OAS) - ribonuclease L (RNAseL) - phosphodiesterase 12 (PDE12) pathway is an essential interferon-induced effector mechanism against RNA virus infection. Inhibition of PDE12 leads to selective amplification of RNAseL activity in infected cells. We aimed to investigate PDE12 as a potential pan-RNA virus antiviral drug target and develop PDE12 inhibitors that elicit antiviral activity against a range of viruses. A library of 18 000 small molecules was screened for PDE12 inhibitor activity using a fluorescent probe specific for PDE12. The lead compounds (CO-17 or CO-63) were tested in cell-based antiviral assays using encephalomyocarditis virus (EMCV), hepatitis C virus (HCV), dengue virus (DENV), West Nile virus (WNV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in vitro. Cross reactivity of PDE12 inhibitors with other PDEs and in vivo toxicity were measured. In EMCV assays, CO-17 potentiated the effect of IFNα by 3 log₁₀. The compounds were selective for PDE12 when tested against a panel of other PDEs and non-toxic at up to 42 mg kg^-1 in rats in vivo. Thus, we have identified PDE12 inhibitors (CO-17 and CO-63), and established the principle that inhibitors of PDE12 have antiviral properties. Early studies suggest these PDE12 inhibitors are well tolerated at the therapeutic range, and reduce viral load in studies of DENV, HCV, WNV and SARS-CoV-2 in human cells and WNV in a mouse model.

01 Jun 2013·Bioorganic & Medicinal ChemistryQ3 · MEDICINE

Synthesis and biological evaluation of Esaprazole analogues showing σ1 binding and neuroprotective properties in vitro

Q3 · MEDICINE

Article

Author: Wellejus, Anja ; Kelly, Nicholas M. ; Weidner, Morten Sloth ; Elbroend-Bek, Heidi ; Joergensen, Signe Humle

Esaprazole, a molecule previously acknowledged to protect against stomach and intestinal ulcers was surprisingly discovered to have neuroprotective activities and σ1 binding in vitro. A highly diverse set of Esaprazole analogues 2-5 was prepared in order to increase blood-brain barrier penetration. The analogues showed a structure-activity relationship at the σ1 receptor closely matching already published pharmacophores. Many of the analogues were shown to have neuroprotective properties in two assays using primary cultures of cortical neurons exposed to glutamate and hydrogen peroxide. However, no apparent SAR for these two assays could be developed. Metabolic stability of the analogues were also investigated and the structure of R(1) had a significant bearing on the ADME properties of the compound resulting in two series of compounds. Compounds in which R(1) was a H or acyl group had good metabolic stability in RLM but poor BBB penetration, whereas compounds where R(1) was a cyclo- or bicyclo-alkyl group had poor metabolic stability but good BBB penetration.

01 Jan 1993·PharmacologyQ4 · MEDICINE

Inhibitory Cholinergic Effects of Esaprazole on Gastric Secretion and Plasma Gastrin Levels in the Dog

Q4 · MEDICINE

Article

Author: Natale, Gianfranco ; Intorre, Luigi ; Del Tacca, Mario ; Mengozzi, Grazia ; Soldani, Giulio ; Blandizzi, Corrado

The effects of esaprazole, a novel antiulcer drug, on gastric acid secretion and plasma gastrin levels were investigated in dogs provided with a gastric fistula or Heidenhain pouch. Esaprazole affected in a different extent the tests performed on dogs with a gastric fistula. The greatest inhibitory effect was obtained against 2-deoxy-D-glucose-induced acid output and gastrin release. An intermediate inhibition by esaprazole was detected on bethanechol-evoked secretion, and the lowest activity was found versus histamine-stimulated secretion. All these responses were strongly inhibited by the antimuscarinic drug pirenzepine used as reference drug. Moreover, both esaprazole and pirenzepine prevented the acid secretory response to a test meal in dogs with a Heidenhain pouch, without significantly affecting plasma gastrin levels. The present results suggest that the depressant action of esaprazole on gastric secretion depends on its peripheral anticholinergic activity, consisting of a partial blockade of acid output and a main reduction of vagally mediated gastrin release. On the basis of these findings, the antiulcer activity of esaprazole might be in part ascribed to its inhibitory effects on gastric secretion.

100 Deals associated with Esaprazole hydrochloride

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Indication	Country/Location	Organization	Date
Peptic Ulcer	IT	Camillo Corvi	12 Jun 1995

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Indication	Highest Phase	Country/Location	Organization	Date
Peptic Ulcer	Preclinical	-	Camillo Corvi	-

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