Novel Hantzsch 1,4-dihydropyridines to study the structure-function relationships of calcium channels and photoinduced relaxation

Abstract

A group of methyl 1,4‐dihydro‐2,6‐dimethyl‐4‐(2‐, 3‐ or 4‐NHOH; 3‐ or 4‐N=O)‐phenyl‐5‐pyridinecarboxylates possessing a C‐3 CO2Me or NO2 substituent [compounds 5–8, 10–12, below] were synthesized by reduction of the C‐4 nitrophenyl precursors [1–4] to the corresponding phenylhydroxylamine [5–8] derivatives using 5% rhodium‐on‐charcoal with hydrazine hydrate as the hydrogen donor, followed by re‐oxidation of the phenylhydroxylamine product [6–8] to the corresponding nitrosophenyl [10–12] derivative using pyridinium chlorochromate. A series of 1,4‐dihydro‐2,6‐dimethyl‐4‐(2‐trifluoromethylphenyl)pyridines [26–34] possessing CO2Me, COMe, CONH2, P(=O)OEt2, CN, NO2 C‐3/C‐5 substituents were synthesized using a modified Hantzsch reaction involving the condensation of 2‐trifluoromethylbenzaldehyde [17] with an aminocrotonate [18–20] and a ketone [21–25] derivative. In vitro calcium channel (CC) activities were determined using a muscarinic‐receptor‐mediated Ca+2‐dependent contraction of guinea pig ileal longitudinal smooth muscle assay. This class of compounds [5–8, 10–12, 26–34] exhibited weak CC antagonist activity [10–4 to 10–7 M range] relative to the reference drug nifedipine [IC50 = 1.4 × 10–8 M]. Structure–activity relationships [SARs] acquired were in agreement with known SARs where the relative potency order for C‐4 phenyl substituents is ortho and meta > para. A C‐3 nitro substituent decreased CC antagonist activity. Compounds 29–34 possessing C‐3 CN or NO2, and a C‐5 CO2Me, NO2, CONH2, COMe, or P(=O)OEt2, substituents exhibited weak CC antagonist activity in the 10–4 to 10–5 M range. Although this group of highly functionalized 1,4‐dihydropyridines are not useful CC antagonists, they will serve as valuable model compounds to study the structure–function relationships of CC modulation. Drug Dev. Res. 42:120–130, 1997. © 1997 Wiley‐Liss, Inc.

Chemical and Pharmacological Significance of 1,4-Dihydropyridines

“…Iqbal et al [33] synthesized novel 1,4-DHP's and studied their SAR. The structure-function relationship of the compounds were in agreement with the known structure-activity relationship, where the relative potency order for C-4 phenyl substitution is ortho>meta>para.…”

Durchführung von chemischen Reaktionen im Mikrowellenfeld

“…Die Synthese von substituierten Dihydropyridinen (Hantzsch-Reaktion) ist eine weitere, seit etwa 100 Jahren bekannte Reaktion [56], welche zu pharmakologisch interessanten Produkten führt [57], s. Schema 4.…”

Molecular modeling and QSAR analysis of some 4,5-dichloroimidazolyl-1,4-DHP-based calcium channel blockers

“…1), the prototype of which is nifedipine, have been the aim of many SAR [6][7][8][9][10] and QSAR studies [11][12][13][14][15][16][17][18][19]. QSAR models are mathematical equations relating chemical structure to their biological activity.…”