Control of irritable bowel syndrome with polyamine analogs: a structure-activity study.
The evaluation of a group of polyamine analogs as agents to ameliorate diarrhea-predominant irritable bowel syndrome is described. Each compound was assessed when administered subcutaneously in a psychological stress-induced model of irritable bowel syndrome in rodents for its ability to reduce stool output in a dose-dependent manner. The spermine pharmacophore is shown to be an excellent platform from which to construct compounds to treat irritable bowel syndrome. 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. In addition to the subcutaneous studies, several compounds, N1,N11-diethylnorspermine, N1,N12-diethylspermine, N1,N12-diisopropylspermine, N1,N14-diethylhomospermine, N,N'-bis[5-(ethylamino)pentyl]-1,4-butanediamine, N,N'-bis[2-(4-piperidinyl)ethyl]-1,4-diaminobutane, and N,N'-bis[3-(ethylamino)propyl]-trans-1,4-cyclohexanediamine, were subsequently evaluated for oral efficacy. The remarkable activity of N,N'-bis[3-(ethylamino)propyl]-trans-1,4-cyclohexanediamine underscores the need to explore this framework further as a pharmacophore for the construction of other analogues to relieve the symptoms of diarrhea-predominant IBS.
Bergeron
R J
RJ
Department of Medicinal Chemistry, University of Florida, Gainesville 32610, USA.
Wiegand
J
J
Fannin
T L
TL
D000818:Animals; D003109:Colonic Diseases, Functional / Q000188:drug therapy* / Q000517:prevention & control; D051379:Mice; D008815:Mice, Inbred Strains; D011073:Polyamines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013096:Spermine / Q000031:analogs & derivatives*; D013329:Structure-Activity Relationship
D011073:Polyamines; C058306:N(1),N(14)-bis(ethyl)homospermine; D013096:Spermine