Thiophenecarboxylate suppressor of cyclic nucleotides discovered in a small-molecule screen blocks toxin-induced intestinal fluid secretion.
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.
Tradtrantip
Lukmanee
L
Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, CA 94143-0521, USA.
Yangthara
Buranee
B
Padmawar
Prashant
P
Morrison
Christopher
C
Verkman
A S
AS
D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000037:antagonists & inhibitors; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D007287:Inorganic Chemicals / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D007419:Intestinal Secretions / Q000378:metabolism*; D007668:Kidney / Q000166:cytology; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D009712:Nucleotides, Cyclic / Q000032:analysis / Q000037:antagonists & inhibitors*; D007690:Polycystic Kidney Diseases / Q000188:drug therapy; D051381:Rats; D011916:Rats, Inbred F344; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013961:Thyroid Gland / Q000166:cytology* / Q000378:metabolism*; D014162:Transfection
D007287:Inorganic Chemicals; D009712:Nucleotides, Cyclic; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D002772:Cholera Toxin; D000242:Cyclic AMP; D006152:Cyclic GMP