Drug repurposing for cardiovascular diseases: New targets and indications for probenecid

Abstract

The available pharmacological options in the management of cardiovascular diseases such as ischaemic heart disease and subsequent heart failure are effective in slowing the progression of this condition. However, the long‐term prognosis is still poor, raising the demand for new therapeutic strategies. Drug repurposing is a time‐ and cost‐effective drug development strategy that offers approved and abandoned drugs a new chance for new indications. Recently, drugs used for the management of gout‐related inflammation such as canakinumab or colchicine have been considered for drug repurposing in cardiovascular indications. The old uricosuric drug, probenecid, has been identified as a novel therapeutic option in the management of specific cardiac diseases as well. Probenecid can modulate myocardial contractility and vascular tone and exerts anti‐inflammatory properties. The mechanisms behind these beneficial effects might be related inhibition of inflammasomes, and to modulation purinergic–pannexin‐1 signalling and TRPV2 channels, which are recently identified molecular targets of probenecid. In this review, we provide an overview on repurposing probenecid for ischaemic heart disease and subsequent heart failure by summarizing the related experimental and clinical data and propose its potential repurposing to treat cardiovascular diseases.

Synthesis of α-cyanato-α′-carbonyl sulfoxonium ylides in water

“…Nonsteroidal anti-inflammatory drugs (NSAIDs) were widely used, [44][45][46][47][48] and we successfully applied our reaction to substrates derived from naproxen, 46,48 loxoprofen, 44 and oxaprozin, 45 yielding the desired products 29b-31b in 60% to 72% yields. Furthermore, substrate 32b derived from probenecid which was widely used as an antigout drug, 49 underwent excel- a Reaction conditions: 1a (0.2 mmol), TsCN(0.4 mmol, 2 eq. ), catalyst (5 mol%) in 2 mL of solvent at 60 °C under air.…”

Age-Dependent Activation of Pannexin1 Function Contributes to the Development of Epileptogenesis in Autosomal Dominant Sleep-related Hypermotor Epilepsy Model Rats

“…It has been established that probenecid and carbenoxolone are non-peptide hemi channel inhibitors [2,[45][46][47]. Probenecid is a relatively selective pannexin1-hemichanne inhibitor [46,48], whereas carbenoxolone is a non-selective inhibitor for the pannexin1 hemichannel, connexin43-hemichannel, gap junctions, and other channels [12,[49][50][51][52][53][54]. To identify the fundamental molecules underlying increased astroglial D-serine release These results suggest that the gating properties of the connexin43-hemichannels are more sensitive to the decreasing extracellular Ca 2+ level compared to the pannexin1hemichannels [23,[25][26][27][28], whereas the sensitivity to membrane depolarization of the pannexin1hemichannels is shown to be dominant compared to the connexin43-hemichannels [22,24,44].…”

“…It has been established that probenecid and carbenoxolone are non-peptide hemichannel inhibitors [2,[45][46][47]. Probenecid is a relatively selective pannexin1-hemichannel inhibitor [46,48], whereas carbenoxolone is a non-selective inhibitor for the pannexin1hemichannel, connexin43-hemichannel, gap junctions, and other channels [12,[49][50][51][52][53][54]. To identify the fundamental molecules underlying increased astroglial D-serine release induced by HFO-evoked stimulation and the removal of extracellular Ca 2+ , the concentrationdependent effects of probenecid and carbenoxolone on astroglial D-serine release were also determined.…”