ArticleMolecular pharmacology2009
Thiophenecarboxylate suppressor of cyclic nucleotides discovered in a small-molecule screen blocks toxin-induced intestinal fluid secretion.
Article in Molecular pharmacology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 23 citations in OpenAlex.
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- Autosomal dominant polycystic kidney disease: Disrupted pathways and potential therapeutic interventions.Journal of cellular physiology · 2019Review
- Management of autosomal-dominant polycystic kidney disease-state-of-the-art.Clinical kidney journal · 2018Review
- Modulation of Polycystic Kidney Disease Severity by Phosphodiesterase 1 and 3 Subfamilies.Journal of the American Society of Nephrology : JASN · 2016Article
- Strategies targeting cAMP signaling in the treatment of polycystic kidney disease.Journal of the American Society of Nephrology : JASN · 2014Review
- Chloride channel-targeted therapy for secretory diarrheas.Current opinion in pharmacology · 2013Review
- Cystic fibrosis transmembrane regulator correctors and potentiators.Cold Spring Harbor perspectives in medicine · 2013Review
- Experimental therapies and ongoing clinical trials to slow down progression of ADPKD.Current hypertension reviews · 2013Review
- Potent, metabolically stable benzopyrimido-pyrrolo-oxazine-dione (BPO) CFTR inhibitors for polycystic kidney disease.Journal of medicinal chemistry · 2011Article
- Treatment strategies and clinical trial design in ADPKD.Advances in chronic kidney disease · 2010Review
- Crofelemer, an antisecretory antidiarrheal proanthocyanidin oligomer extracted from Croton lechleri, targets two distinct intestinal chloride channels.Molecular pharmacology · 2010Article
- Cyclic nucleotide signaling in polycystic kidney disease.Kidney international · 2010Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
We carried out a "pathway" screen of 50,000 small molecules to identify novel modulators of cAMP signaling. One class of compounds, the 2-(acylamino)-3-thiophenecarboxylates, strongly suppressed cAMP and cGMP in multiple cell lines in response to different agonists acting on G-protein-coupled receptors, adenylyl cyclase, and guanylyl cyclase. The best compounds from structure-activity analysis of 124 analogs, including several synthesized chiral analogs, had and IC(50) of <5 microM for suppression of agonist-induced cAMP and cGMP elevation. Measurements of cAMP, cGMP, and downstream signaling in response to various activators/inhibitors suggested that the 2-(acylamino)-3-thiophenecarboxylates function as nonselective phosphodiesterase activators, although it was not determined whether their action on phosphodiesterases is direct or indirect. The 2-(acylamino)-3-thiophenecarboxylates suppressed CFTR-mediated Cl(-) current in T84 colonic cells in response to cholera and Escherichia coli (STa) toxins, and prevented intestinal fluid accumulation in a closed-loop mouse model of secretory diarrhea. They also prevented cyst growth in an in vitro renal epithelial cell model of polycystic kidney disease. The 2-(acylamino)-3-thiophenecarboxylates represent the first small-molecule cyclic nucleotide suppressors, whose potential therapeutic indications include secretory diarrheas, polycystic kidney disease, and growth inhibition of cAMP-dependent tumors.
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