Amlodipine, structure

Bauerle and Seelig [395] studied the structural aspects of amlodipine (weak base, primary amine pKa 9.26 [162]) and nimodipine (nonionizable) binding to phospholipid bilayers, using NMR, microcalorimetry, and zeta-potential measurements. They were able to see evidence of interactions of amlodipine with the cis double bond in the acyl chains. They saw no clear evidence for (=P—O- 1 H N—) electrostatic interactions. 

Fig. 4.8 Structures of the dihydropyridine calcium channel blockers, nifedipine (neutral) and amlodipine (basic).

Bepridil also inhibits fast sodium inward channels. Galcium channel blockers are classified by structure as follows Diphenylalkylamines - verapamil benzothiazepines - diltiazem dihydropyridines - amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine. 

During the course of a study of the salts formed by saccharin with quinine, haloperidol, mirtazapine, pseudoephedrine, lamivudine, risperidone, sertraline, venlafaxine, zolpidem, and amlodipine, a 1 1 cocrystal of saccharin and piroxicam was detected [68]. In the crystal structure, the asymmetric unit was found to consist of one saccharin molecule and one zwitterionic piroxicam molecule that were linked by two sets of N—H O hydrogen bonds. The piroxicam-saccharin synthons were in turn linked through bridging C—H O hydrogen bonds. Interestingly, the drug substance solubility out of the cocrystal was found to be comparable to that of the marketed piroxicam product. 

Fig. 2.2 Chemical structures of amlodipine (1), 5-phenylvaleric acid (2), 4-phenylbutylamine (3), and 5-hydroxyquinoline (4). (Reprinted from ref. 45 with permission from the American Pharmaceutical Association.)...

There are approximately a dozen calcium channel antagonists marketed in the United States for the treatment of hypertension, certain dysrhythmias, and some forms of angina (see Chaps. 13,15, and 17). The calcium channel blockers are classified by their chemical structure as phenylalkylamines (e.g., verapamil), benzothiapines (e.g., diltiazem), and dihydropyridines (e.g., amlodipine, felodipine, nicardipine, and nifedipine). Several of these agents, namely, diltiazem, nicardipine, nifedipine, and verapamil, are formulated as sustained-release oral dosage forms or have a slow onset of action and longer half-life (e.g., amlodipine " ), allowing once-daily administration. 

The 10 Ca -channel antagonists that are approved for clinical use in the United States have diverse chemical structures. Five classes of compounds have been examined phenylalkylamines, dihydropyridines, benzothiazepines, diphenylpiperazines and a diarylaminopropylamine. At present, verapamil (a phenylalkylamine) diltiazem (a ben-zothiazepine) nifedipine, amlodipine, felodipine, isradipine, nicardipine, nisoldipine, and nimodipine (dihydropyridines) and bepridil (a diarylaminopropylamine ether used only for refractory angina) are approved for clinical use in the United States. 

Beresford, A.P. Macrae, P.V. Alker, D. Kobylecki, R.J. Biotransformation of amlodipine. Identification and synthesis of metabolites found in rat, dog and human urine/confirmation of structures by gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry. Arzneimittelfor-schung, 1989, 39, 201-209... 

Fig. 1.12 Open (PDB 3UA5) and closed (PDB 3IBD) conformations of human CYP2B6. The open structure has two molecules of amlodipine spheres) with one molecule of amlodipine bound to the heme iron via nitrogen coordination and the second amlodipine in the open-substrate access channel. The closed structure has one molecule of...

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