Pyridopyrimidine derivatives as inhibitors of cyclic nucleotide synthesis: Application for treatment of diarrhea.
Acute secretory diarrhea induced by infection with enterotoxigenic strains of Escherichia coli involves binding of stable toxin (STa) to its receptor on the intestinal brush border, guanylyl cyclase type C (GC-C). Intracellular cGMP is elevated, inducing increase in chloride efflux and subsequent accumulation of fluid in the intestinal lumen. We have screened a library of compounds and identified a pyridopyrimidine derivatives {5-(3-bromophenyl)-1,3-dimethyl-5,11-dihydro-1H-indeno[2',1':5,6]pyrido[2,3-d]pyrimidine-2,4,6-trione; BPIPP} as an inhibitor of GC-C that can suppress STa-stimulated cGMP accumulation by decreasing GC-C activation in intact T84 human colorectal carcinoma cells. BPIPP inhibited stimulation of guanylyl cyclases, including types A and B and soluble isoform in various cells. BPIPP suppressed stimulation of adenylyl cyclase and significantly decreased the activities of adenylyl cyclase toxin of Bordetella pertussis and edema toxin of Bacillus anthracis. The effects of BPIPP on cyclic nucleotide synthesis were observed only in intact cells. The mechanism of BPIPP-dependent inhibition appears to be complex and indirect, possibly associated with phospholipase C and tyrosine-specific phosphorylation. BPIPP inhibited chloride-ion transport stimulated by activation of guanylyl or adenylyl cyclases and suppressed STa-induced fluid accumulation in an in vivo rabbit intestinal loop model. Thus, BPIPP may be a promising lead compound for treatment of diarrhea and other diseases.
Institute of Molecular Medicine, University of Texas Health Science Center, 1825 Pressler Street, Houston, TX 77030, USA.
Alexander Y
AY
Kots
Byung-Kwon
BK
Choi
Maria E
ME
Estrella-Jimenez
Cirle A
CA
Warren
Scott R
SR
Gilbertson
Richard L
RL
Guerrant
Ferid
F
Murad
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D000930:Antidiarrheals / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D001427:Bacterial Toxins / Q000494:pharmacology; D002460:Cell Line; D006224:Cricetinae; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006152:Cyclic GMP / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003967:Diarrhea / Q000188:drug therapy* / Q000201:enzymology; D004768:Enterotoxins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D029968:Escherichia coli Proteins; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D051381:Rats; D054852:Small Molecule Libraries
C530072:5-(3-bromophenyl)-1,3-dimethyl-5,11-dihydro-1H-indeno(2',1'-5,6)pyrido(2,3-d)pyrimidine-2,4,6-trione; D000067956:Adenylyl Cyclase Inhibitors; D000930:Antidiarrheals; D001427:Bacterial Toxins; D004768:Enterotoxins; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; D054852:Small Molecule Libraries; C034151:heat stable toxin (E coli); D000242:Cyclic AMP; D006162:Guanylate Cyclase; D006152:Cyclic GMP