synthesis and in vitro pharmacology of a series of histamine h2 ...

Chapter 2
Figure 28: 1,4-Dihydropyridines with nitrate ester moieties
Increasing the alkyl chain length from ethyl to tetradecyl showed an optimum in
relaxation of KCl-induced contractions in rat aorta for the hexyl and octyl derivatives
(PIC50 = 8.0), while the highest DHP-receptor affinity was found for the tetradecyl
derivative (pKj = 9.7; displacement of [ 3
H]nitrendipine from rat cortex membranes). It
is not possible to determine the individual contribution to vasodilation of nitrate
esters and calcium channel blockers, because of their synergistically mechanism of
actions.
Numerous 1,4-DHPs with one or two nitrate ester groups on the C3 and/or C5
position on the 1,4-DHP ring have been synthesized 46
activity relationship studies 47
resulting in CD-349 48
and evaluated in structure-
(fig. 29). CD-349 is a potent
vasodilator. Besides its actions as an antihypertensive agent, CD-349 appeared to be
a potent cerebrovasodilator in dogs 49
treatment of cerebrovascular disorders in human.
Figure 29: CD-349
and cats 50
, and, therefore, could be useful in the
The synthesis of the stereoisomers of CD-349 is currently under investigation 51
might reveal whether the cardiovascular and cerebrovascular actions reside in the
same stereoisomer.
Nicorandil (fig. 30), originally developed as a nitrovasodilator, can be considered as a
hybrid molecule combining a nitrate ester function with a potassium channel
activating moiety. The profound antianginal effects of nicorandil are ascribed to the
58
and