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Design and syntheses of C‐4 4‐(1‐methoxycarbonyl‐1,2‐dihydropyridyl)‐, and 3‐[1‐methoxycarbonyl‐1,2‐(and 1,6‐)dihydropyridyl]‐, derivatives of alkyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐5‐pyridinecarboxylates with cardiospecific calcium channel agonist activity
Author(s) -
Ramesh Manian,
Matowe Wandikayi C.,
Wolowyk Michael W.,
Knaus Edward E.
Publication year - 2000
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/1098-2299(200004)49:4<245::aid-ddr3>3.0.co;2-#
Subject(s) - chemistry , alkyl , stereochemistry , medicinal chemistry , organic chemistry
Abstract A group of hitherto unknown alkyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(dihydropyridyl)‐5‐pyridinecarboxylates possessing 4‐[4‐(1‐methoxycarbonyl‐1,2‐dihydropyridyl)]‐ (6–10), or 4‐[3‐(1‐methoxycarbonyl‐1,2‐(and 1,6‐)dihydropyridyl)]‐ (16–20), moieties were synthesized by reaction of the 4‐(4‐pyridyl)‐ (1–5), or 4‐(3‐pyridyl)‐ (11–15), precursors with methyl chloroformate in the presence of sodium borohydride. In vitro calcium channel (CC) antagonist activities were determined using a muscarinic‐receptor‐mediated Ca 2+ ‐dependent contraction of guinea pig ileal longitudinal smooth muscle (GPILSM) assay. Elaboration of the 4‐pyridyl (1–5), or 3‐pyridyl (11–16), substituent to the corresponding 1,2‐(1,6)dihydropyridyl moiety abolished the CC agonist effect produced by 1–5 and 11–15 on GPILSM. In addition, all alkyl esters possessing a 4‐[4‐ or 3‐(1‐methoxycarbonyl‐1,2‐(1,6‐)dihydropyridyl)]‐ moiety (6–10, 17, 19–20) were inactive CC antagonists on GPILSM with the exception of the ethyl (16) and isobutyl (18) ester derivatives, which exhibited weak CC antagonist activity. All of the 4‐[4‐ or 3‐(1‐methoxycarbonyl‐1,2‐(1,6‐)dihydropyridyl)] compounds evaluated (6–10, 16–19) exhibited in vitro CC agonist (positive inotropes) activity on guinea pig left atria (GPLA). In general, the 4‐[3‐(1‐methoxycarbonyl‐1,2‐(and 1,6)dihydropyridyl)] compounds (16–19) were more potent CC agonists (EC 50 = 2.91 × 10 –6 to 7.51 × 10 –6 M range) than the corresponding 4‐[4‐(1‐methoxycarbonyl‐1,2‐dihydropyridyl)] compounds (6–9, EC 50 = 1.42 × 10 –5 to 2.65 × 10 –5 M range). These 4‐[4‐ or 3‐(1‐methoxycarbonyl‐1,2‐(1,6)dihydropyridyl)] compounds, which exhibit cardiospecific CC agonist activity (6–10, 17, 19) will serve as valuable model compounds to study the structure–function relationships of CC modulation, and provide a new drug design concept directed toward the treatment of congestive heart failure. Drug Dev. Res. 49:245–252, 2000. © 2000 Wiley‐Liss, Inc.