Polyamine analogue antidiarrheals: a structure-activity study.
The syntheses of a group of spermine polyamine analogues and their evaluation as antidiarrheals are described. Each compound was assessed in a rodent castor oil-induced diarrhea model for its ability to reduce stool output and weight loss in a dose-dependent manner. The spermine pharmacophore is shown to be an excellent platform from which to construct antidiarrheals. The activity of the compounds is very dependent on both the nature of the terminal alkyl groups and the geometry of the methylene spacers separating the nitrogens. The toxicity profile is also quite dependent on these same structural features. On the basis of subcutaneous dose-response data and toxicity profiles, two compounds, N(1),N(12)-diisopropylspermine and N(1),N(12)-diethylspermine, were taken forward into more complete evaluation. These measurements included formal acute and chronic toxicity trials, drug and metabolic tissue distribution studies, and assessment of the impact of these analogues on tissue polyamine pools. Finally, the remarkable activity of N,N'-bis[3-(ethylamino)propyl]-trans-1,4-cyclohexanediamine underscores the need to further explore this framework as a pharmacophore for the construction of other antidiarrheal agents.
Bergeron
R J
RJ
Department of Medicinal Chemistry, University of Florida, J. Hillis Miller Health Science Center, Gainesville, Florida 32610, USA. begeron@mc.cop.ufl.edu
Wiegand
J
J
McManis
J S
JS
Weimar
W R
WR
Smith
R E
RE
Algee
S E
SE
Fannin
T L
TL
Slusher
M A
MA
Snyder
P S
PS
D000284:Administration, Oral; D000818:Animals; D000930:Antidiarrheals / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D002368:Castor Oil; D003514:Cyclohexylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D003967:Diarrhea / Q000139:chemically induced / Q000188:drug therapy; D004285:Dogs; D005260:Female; D007928:Lethal Dose 50; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D013096:Spermine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D023382:Toxicity Tests, Acute
D000930:Antidiarrheals; D003514:Cyclohexylamines; C421917:N,N'-bis(3-(ethylamino)propyl)-1,4-cyclohexanediamine; D013096:Spermine; D002368:Castor Oil