Synthesis and calcium channel modulation effects of isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-phenylpyridine-5-carboxylates possessing ortho-, meta-, and para-CH2S(O)nMe and -S(O)nMe (n=0-2) phenyl substituents

A group of isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-phenyl (13-15) poss essing ortho-, meta-, and para-CH2S(O)nMe and -S(O)nMe (n = 0-2) phenyl sub stituents were synthesized using a modified Hantzsch reaction. Calcium chan nel (CC) modulating activities were determined using guinea pig ileum longi tudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) in vitro a ssays. This class of -CH2S(O)nMe and -S(O)nMe (n = 0-2) compounds (13-15a-f ) exhibited weaker CC antagonist activity on GPILSM (IC50 = > 1.1 x 10(-5) to 4.1 x 10(-6) M range) than the reference drug nifedipine (IC50 = 1.4 x 1 0(-8) M). The oxidation state of the sulfur atom was a determinant of smoot h muscle CC antagonist activity where the relative activity profile was gen erally thio (13, -CH2SMe, -SMe) and sulfonyl (15, -CH2SO2Me, -SO2Me) > sulf inyl (14, -CH2SOMe, -SOMe). The point of attachment of the phenyl substitue nt was a determinant of activity for the -CH2SMe (13a-c), -CH2SOMe (14a-c) and SOMe (14d-f) isomers where the relative potency order was meta and para > ortho. Compounds in this group (13-15), unlike Bay K 8644 (EC50 = 2.3 x 10(-7) M on GPILSM), did not exhibit an agonist effect on GPILSM. The meta- CH2SMe (13b), ortho-CH2SMe (13c), meta-SMe (13e), and ortho-CH2SO2Me (15c) C-4 phenyl derivatives exhibited respectable in vitro cardiac positive inot ropic activities (EC50 = 1.00 x 10(-6) to 7.57 x 10(-6) M range) relative t o the reference drug Bay K 8644 (EC50 = 7.70 x 10(-7) M) in the GPLA assay. In contrast to Bay K 8644, which acts as an undesirable calcium channel ag onist on smooth muscle (GPILSM), compounds 13b (IC50 = 4.11 x 10(-6) M), 13 c (IC50 = 2.29 x 10(-5) M), 13e (IC50 = > 1.20 x 10(-5) M) and 15c (IC50 = 6.22 x 10(-6) M) exhibited a desirable simultaneous calcium channel antagon ist effect on smooth muscle at a similar (13b, 15c), or lower (13c, 13e), c oncentration relative to its cardiac agonist EC50 value. Model compounds su ch as 13b, 13c, 13e, and 15c, that exhibit dual cardioselective agonist / s mooth muscle selective antagonist activities, represent a novel type of 1,4 -dihydropyridine CC modulators that offer a potential approach to drug disc overy targeted toward the treatment of congestive heart failure and for use as probes to study the structure-function relationship of calcium channels . Drug Dev. Res. 51:177-186, 2000. (C) 2001 Wiley-Liss, Inc.