Calcium Ion Channels and Their Blockers - Ion Channels and Their Inhibitors - page 276

Mahmoudian and Richard [ 70 ] conducted a Hansch analysis on a subset of
4-phenyl-substituted dihydropyridines (Fig. 2 ) and found that bulky and lipophilic
groups at the ortho -position and ortho -bulky groups with high Hammet electronic
constant (

) at the meta- position of the 4-phenyl ring increase the activity.
From a Hansch analysis for a series of ortho -analogs (Fig. 2 ), [ 66 ] steric
hindrance of the substituents (as Verloop parameter B 1 ) was shown to be significant
for the calcium ion channel blocking activity. No relationship was indicated for
either electronic or lipophilic properties. Since the biological response increases
as B 1 increases, steric hindrance in the ortho -position is required to fix the
dihydropyridine core into a favorable conformation in which the aromatic moiety
is approximately perpendicular to the dihydropyridine ring.
A QSAR study was applied on a large number of 4-phenyl-substituted nifedipine
analogs (Fig. 2 )[ 71 ] by the combination of substituent constants and molecular
descriptors. QSAR analysis showed that a dominant steric effect (as V w van der
Waals volume) can be produced from the para position [ 71 ]. For all mono-para
substituted analogs, the bulky substituents will be dentrimental to the activity, and
this was also shown by Berntsson and Wold [ 72 ] in a study on the binding affinity of
a small set of compounds. The same researchers had observed that the activity
will be increased by the presence of electron withdrawing substituents on the ring.
It was found that the activity of meta -substituted analogs is affected by both steric
and electronic parameters, whereas the hydrophobic and electronic parameters
of the para -substituted analogs affect the activity. Hansch analysis has been
applied for nifedipine analogs containing nitroimidazolyl, phenylimidazolyl, and
methylsulphonyl-imidazolyl groups at the C-4 position and different ester
substituents at C-3 and C-5 positions of the ring. The results showed that
Hammett's electronic and hydrophobic properties are highly correlated with the
biological activity [ 73 ].
In a series of sulfonylindolizines (Fig. 9 ), Gupta et al. [ 74 ] recently showed,
through a QSAR study, that the presence of different heterocyclic rings in different
compounds could affect the activity altering the conformations of the receptor
through their steric properties.
In 2009, Miri et al. [ 75 ] synthesized a novel group of bis-1, 4-dihydropyridines
using the condensation of n -alkyl diacetoacetate ( n

s

¼ 2-7) with methyl-3-

aminocrotonate and nitrophenylaldehyde (Fig. 10 ).

R 1

R 1 = NO 2 , Cl, CF 3
R 2 = Me, CH 2 CH 2 N(CH 3 )Bn, CH 2 Ph, CH 2 CHCH 2 , CH 2 CH 2 N(CH 3 ) 2
R 3 = Me, Et, iPr, sBu, CH 2 CH 2 N(CH 3 )Bn

COOR 3

R 2 X N

H

Me

Fig. 9 Sulfonylindolizines