Dihydropyridines structure-activity relationship

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. 

A series of pyrazolo[3,4-, pyridazinones 430 and analogues, potentially useful as peripheral vasodilators, were synthesized and evaluated as inhibitors of PDE5 extracted from human platelets. Several of them showed ICso values in the range 0.14-1.4 pM. A good activity and selectivity profile versus PDE6 was found for compound 430 (6-benzyl-3-methyl-l-isopropyl-4-phenylpyrazolo[3,4-r/]pyridazin-7(6/7)-one). Structure-activity relationship studies demonstrated the essential role played by the benzyl group at position 6 of the pyrazolopyridazine system. Other types of pyridazinones fused with five- and six-membered heterocycles (pyrrole, isoxazole, pyridine, and dihydropyridine), as well as some open-chain models were prepared and evaluated. Besides the pyrazole, the best of the fused systems proved to be isoxazole and pyridine <2002MI227>. 

Zhou XF, Shao Q, Coburn RA, Morris ME (2005) Quantitative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 1,4-dihydropyridines and pyridines as multidrug resistance modulators. Pharm Res 22 1989-1996... 

Voigt B, Coburger C, Monar J, Andreas H (2007) Structure-activity relationships of novel W-acyloxy-1,4-dihydropyridines as P-glycoprotein inhibitors. Biorg Med Chem 15 5110-5120... 

Alker D, Campbell SF, Cross PE et al (1990) Long-acting dihydropyridine calcium antagonists. 4. Synthesis and structure-activity relationships for a series of basic and non basic derivatives of 2[(2-aminoethoxy)methyl]-l, 4-dihydropyridine calcium antagonists. J Med Chem 33 585-591... 

Quantitative structure-activity relationship Phenylalkylamines - 1,4-Dihydropyridines Benzothiazepines Verapamil Nifedipine DUtiazem Dihydropyrimidines ... 

However, the studies on the calcium channel blockers remained centered even today around the l,4-dihydropyridine class. Since this class of compounds can also act as calcium channel activators, attention has always been drawn towards their structure-activity relationship studies. Attempts were made to differentiate in the mechanisms of their agonist and antagonist activities. On the basis of the force field and quantum mechanical calculations, Holtze and Marrer [51] discovered a imique area of the molecular potentials where Ca agonists and antagonists possess potential of opposite sign. These authors demonstrated that the molecular potential of a simple receptor site was reduced by interaction with calciiun channel activators and, on the contrary, increased by interaction with calcium channel blockers. These opposite effects probably could be the basis for the opposite actions of DHP enantiomers at the potential-dependent calcium channel. 

A quantitative structure-activity relationship of 1,4-dihydropyridine calcium channel blockers with electronic descriptors produced by quantum chemical topology... 

Hemmateenejad B, Akhond M, Miri R, Shamsipur M. Quantitative structure-activity relationship study of recently synthesized 1,4-dihydropyridine calcium channel antagonists. In Application of the Hansch analysis method. Weinheim Arch Pharm, 2002. p. 472-80. 

Takahata Y, Costa MC, Gaudio AC. Comparison between neural networks (NN) and principal component analysis (PCA) Structure activity relationships of 1,4-dihydropyridine calcium channel antagonists (nifedipine analogues). J Chern Inf Comput Sci 2003 43 540-4. 

Kharkar PS, Desai B, Gaveria H, Varu B, Loriya R, Naliapara Y, et al. Three-dimensional quantitative structure-activity relationship of 1,4-dihydropyridines as antitubercular agents. J Med Chem 2002 45 4858-67. 

Pedemonte, N., Boido, D., Moran, O., Giampieri, M., Mazzei, M., Ravazzolo, R., Galietta, L. J. Structure-activity relationship of 1, 4-dihydropyridines as potentiators of the CFTR chloride channel. Mol. Pharmacol. 2007, 23. [Epub ahead of print]. 

A quantitative structure-activity relationship for the negative inotropic activity of a small series of 1,4-dihydro-pyridines has been developed (47.). For 2,6-dimethyl-3,5-dicarbo-methoxy-4-(substituted phenyl)-1,4-dihydropyridines the effect of the phenyl substituent is determined primarily by steric effects. Thus, for ortho-substituted derivatives,... 

The existence of such structure-activity relationships is consistent with a specific, rather than a non-specific, site of action. Additional support is provided by the stereoselectivity of action exhibited by verapamil/D600 and by several agents of the 1,4-dihydropyridine class. 

Quantitative structure-activity relationships have been determined for some of the 1,4-dihydropyridines. Hansch analysis reveals significant correlations between negative inotropy and (a) minimum width (i.e., or/Ao-substituted phenyl derivatives), (b) van der Waals s volume (ester-substituted derivatives) and (c) lipophilicity (ester derivatives) [76]. 

Takahata Y, Gaudio AC, Korolkovas A. Quantitative structure-activity relationships for calcium antagonist 1,4-dihydropyridine (nifedipine analogues) derivatives a quantum chemical/classical approach. J Pharm Sci 1994 83 1110-1115. 

The local anesthetic agents interacting at Na channels provide an example of quantitative changes in structure-activity relationships as a function of channel state. The 1,4-dihydropyridines interacting at the L-type of voltage-gated Ca channel provide an example where both... 

Bossert and co-workers original three-component Hantzsch synthesis of nifedipine used 1 equiv of 2-ntirobenzaldehyde 181, 2 equiv of methyl acetoacetate 180, and ammonia to give nifedipine in 72% yield. Since their report, a number of variations on the Hantzsch 1,4-dihydropyridine synthesis have been reported. Many of the initial reports on the synthesis of 1,4-dihydropyridine derivatives were aimed at studying the structure activity relationships of these compounds with the goal of developing more potent and specific analogs of nifedipine. 

H.-D. Holtje and S. Marrer, Quant. Struct.-Act. Relat., 7, 174 (1988). Qualitative and Quantitative Structure—Activity Relationships for Calcium Channel Modulating 1,4-Dihydropyridine Derivatives A Hypothetical Molecular Receptor Model. 

The structure activity relationship developed for these dihydropyridines showed that optimal activity was derived from BTF, using anilines containing a halogen, cyano or CFj group in the para position and small aliphatic and cyclic ketones and acetophenones. 

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). 

---