Dihydropyridines, calcium channel blocking

Figure 9 Structures of chiral 1,4-dihydropyridine calcium channel blocking agents.

This section deals with the application of molecular orbital (MO) calculations in structure-activity relationship (SAR) analyses. Calcium channel-blocking 1,4-dihydropyridine (DHP) derivatives such as nifedipine (Fig. 9.10) are widely used in the therapy of cardiovascular disorders. 

Hypersensitivity to the drug hypersensitivity to dihydropyridine calcium channel blockers (nisodipine) sick sinus syndrome or second- or third-degree AV block... 

The substitution pattern of the 4-aromatic residue is also important for the activity, the ortho-substitution being the best one in terms of potency and selectivity. A Hansch analysis on a series of ortho-derivatives has shown a significant correlation between calcium antagonist activity and steric hindrance of the substituent, while no relationship was found for either electronic or lipophilic parameters [3]. The best SAR correlation was obtained when the B1 steric parameter (the Verloop parameter) was introduced into the analysis [4]. The calcium channel-blocking activity increases as B1 increases, which probably indicates that steric hindrance in the ortho-position is required to fix the dihydropyridine structure into a favorable conformation in which the aromatic group is approximately perpendicular to the dihydropyridine ring (Fig. 7.12). 

The Hantzsch pyridine synthesis is an old discovery (1882) which sprang into prominence in the 1980s with the discovery that the dihydropyridine intermediates prepared from aromatic aldehydes are calcium channel blocking agents and therefore valuable drugs for heart disease with useful effects on angina and hypertension. 

Shudo N, Mizoguchi T, Kiyosue T, Arita M, Yoshimura A, Seto K, Sakoda R, Akiyama S (1990) Two pyridine analogues with more effective ability to reverse multidrug resistance and with lower calcium channel-blocking activity than their dihydropyridine counterparts. Cancer Res 50 3055-3061... 

Unsymmetrical ester substitutions at C3 and C5 result in chirality at C4 of the dihydropyridines. Separation of pharmacological actions is seen in appropriately structures optical isomers of chiral dihydropyridines. Further, the availability of a boat-like conformation of the dihydropyridines has been proposed to facilitate the calcium channel blocking activity of this class of agents. 

The calcium channel blocking dihydropyridine drugs 17, used in the important field of heart disease and easily prepared by the Hantszch pyridine synthesis, are chiral but only just. The molecule does not quite have a plane of symmetry, because there is a methyl ester on one side and an ethyl on the other and because R may not be Me. An important example is amlodipine 18, a best seller from Pfizer, and this is more asymmetrical than some. Nevertheless resolving these compounds is difficult. 

Barbato, F., Grumetto, L., and Monica, P. (1994) Analysis of calcium channel blocking dihydropyridines and their degradation products by gas chromatography, Farmaco, 49, 461 166. 

The structural features leading to optimal activity of the 1,4-dihydropyridines have been studied in detail. This group comprises the largest number of calcium channel blocking drugs and the individual compounds vary both in potency and selectivity. 1,4-Dihydropyridine compounds have been developed which show agonist effects at the calcium channel. 

Kass RS and Arena JP, Influence of pHo on calcium channel block by amlodipine, a charged dihydropyridine compound. Implications for location of the dihydropyridine receptor, /. Gen. Physiol, 93(6), 1109-1127 (1989). NB Although the pRg is repeatedly stated as 8.6, no experimental detail is given, nor any reference. The paper also claims an estimated pK value of <3.5 for nisoldipine (ref Hugenholtz PC and Meyer J (eds.), Nisoldipine, Springer-Verlag, Berlin, 3-348 (1987). 

---