- A substituted phenyl ring at the C4 position optimizes activity; substitution with
heteroaromatic rings (e.g., pyridine) produces similar efficacy but enhances toxicity;
substitution with nonplanar alkyl or cycloalkyl groups reduces activity - Phenyl ring substitution is crucial for size and location; ortho-ormeta-substituents
confer optimal activity by providing sufficient bulk to “lock” the conformation such
that the C4 phenyl ring is perpendicular to the DHP ring
Extensive theoretical molecular modelling studies have permitted these SARs to be
deduced.
Structural studies have also enabled Ca^2 +channel agonists to be discovered. For
example, Ca^2 +channel agonists were also found among dihydropyridines. BAY K 8644
(7.46; methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(-2-trifluoromethylphenyl)-pyridine-
5-carboxylate) and PN 202-791 (7.47; isopropyl-1,4-dihydro-2,6-dimethyl-3-nitro-
4-(2,1,3-benzoxadiazol-4-yl)-pyridine-5-carboxylate) cause vasoconstriction and also
positive inotropy (an increase in the force of contraction). The latter occurs because the
increase in Ca^2 +influx prolongs the plateau phase of the cardiac action potential. In
theory, such compounds are potential drugs for the treatment of congestive heart failure.
Both these compounds are extremely stereoselective: the S enantiomers are agonists,
whereas the R enantiomers are antagonists of calcium channels. Such opposite effects
are unusual, because normally one enantiomer is the eutomer, the other one the inactive
distomer, not an antagonist. Structural chemistry studies have shown that when the
C3 ester is replaced with an electron-withdrawing group such as NO 2 , the resulting
compounds (such as PN 202-791) are channel activators rather than antagonists.
The 1,4-dihydropyridine “nucleus” has been quite successful as a platform about
which to design drugs. The ability of this nucleus to be absorbed and distributed
throughout the body is well understood. Because of these data, the 1,4-DHP nucleus is
emerging as a preferred platform in drug design. 1,4-DHPs are being used in the design
of therapeutics that do not bind to Ca^2 +channels and that do not exhibit efficacy in car-
diovascular disorders. Also, arising from the importance of Ca^2 +ion to so many other
processes in both human and non-human physiology, Ca^2 +channel blockers are being
evaluated for disorders other than those of a cardiovascular nature. For example, Ca^2 +
channel blockers have been studied as a potential therapeutic approach to the treatment
of chloroquine-resistant malaria. Given the international spread of malaria arising from
the problem of global warming, new, creative approaches to the treatment of malaria
will be desperately needed in coming years.
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