NOVEL HANTZSCH 1,4-DIHYDROPYRIDINES TO STUDY THE STRUCTURE-FUNCTION-RELATIONSHIPS OF CALCIUM CHANNELS AND PHOTOINDUCED RELAXATION

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 sub stituent [compounds 5-8, 10-12, below] were synthesized by reduction o f the C-4 nitrophenyl precursors [1-4] to the corresponding phenylhydr oxylamine [5-8] derivatives using 5% rhodium-on-charcoal with hydrazin e hydrate as the hydrogen donor, followed by re-oxidation of the pheny lhydroxylamine product [6-8] to the corresponding nitrosophenyl [10-12 ] derivative using pyridinium chlorochromate. A series of -2,6-dimethy l-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-trifluor omethylbenzaldehyde [17] with an aminocrotonate [18-20] and a ketone [ 21-25] derivative. In vitro calcium channel (CC) activities were deter mined using a muscarinic-receptor-mediated Ca+2-dependent contraction of guinea pig ileal longitudinal smooth muscle assay. This class of co mpounds [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 x 10(-8) M]. Structure-activity relationships [SARs] acquired w ere in agreement with known SARs where the relative potency order for C-4 phenyl substituents is ortho and meta > para. A C-3 nitro substitu ent decreased CC antagonist activity. Compounds 29-34 possessing C-3 C N or NO?, 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 ar e not useful CC antagonists, they will serve as valuable model compoun ds to study the structure-function relationships of CC modulation. (C) 1997 Wiley-Liss, Inc.