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.