Thiophenecarboxylate Suppressor of Cyclic Nucleotides Discovered in a Small-Molecule Screen Blocks Toxin-Induced Intestinal Fluid Secretion

• Published in: Molecular pharmacology Vol. 75; no. 1; pp. 134 - 142
• Main Authors: Tradtrantip, Lukmanee, Yangthara, Buranee, Padmawar, Prashant, Morrison, Christopher, Verkman, A.S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2009; American Society for Pharmacology and Experimental Therapeutics
• Subjects: Animals; Cell Line; Cells, Cultured; CHO Cells; Cholera Toxin - antagonists & inhibitors; Cricetinae; Cricetulus; Cyclic AMP - metabolism; Cyclic GMP - metabolism; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Disease Models, Animal; Dogs; Inorganic Chemicals - chemical synthesis; Inorganic Chemicals - chemistry; Inorganic Chemicals - metabolism; Intestinal Secretions - metabolism; Kidney - cytology; Mice; Mice, Inbred Strains; Molecular Structure; Nucleotides, Cyclic - analysis; Nucleotides, Cyclic - antagonists & inhibitors; Polycystic Kidney Diseases - drug therapy; Rats; Rats, Inbred F344; Stereoisomerism; Structure-Activity Relationship; Thyroid Gland - cytology; Thyroid Gland - metabolism; Transfection
• DOI: 10.1124/mol.108.050567
• ISSN: 0026-895X; 1521-0111

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 IC50 of <5 μM 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.