Synthesis and activity of 1,4-dihydropyridine analogues of histamine H2-receptor antagonists.
Compounds of the type Het-CH2-S-CH2-CH2-Y were prepared, in which Het was 2-, 3- or 4-pyridyl, and Y was a derivative of 2-cyano-1,1-iminodiamine or 2-nitro-1,1-ethenediamine in which the terminal nitrogen was incorporated into a 1,4-dihydropyridine ring (general structure 7; X = NCN or CHNO2). Pharmacological testing using the histamine-induced guinea pig atrial chronotropic response indicated that the pyridyl substituent position was a determinant of activity, the activity order within each isomeric series being usually 2-pyridyl greater than 3- and 4-pyridyl. There was no significant difference in activity between otherwise similar compounds derived from 2-cyano-1,1-iminodiamine (7, X = NCN) or 2-nitro-1,1-ethenediamine (7, X = CHNO2). All compounds had a substituent (R) attached to the C-4 position of the dihydropyridine ring, and the nature of the R substituent influenced the H2-antagonist activity, the relative activity order being usually n-Bu greater than Ph greater than Me. In general, the incorporation of the terminal nitrogen into a 1,4-dihydropyridyl ring system favoured biological activity, 1-(2-[(4-Pyridylmethylthio)ethylamino])-1-(1-[3-(4, 4-dimethyloxazolin-2-yl)-4-n-butyl-1,4-dihydropyridyl)-2- cyanoimine (7f) was the most potent H2-receptor antagonist exhibiting an activity approaching that of cimetidine.
Agrawal
V K
VK
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Tang
S B
SB
Wolowyk
M W
MW
Knaus
E E
EE
D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006635:Histamine H2 Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male
D004095:Dihydropyridines; D006635:Histamine H2 Antagonists