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Synthesis, Calcium Channel Antagonist Activity, and Anticonvulsant Activity of 3‐Ethyl 5‐Methyl 1,4‐Dihydro‐2‐[(2‐hydroxyethoxy)methyl]‐6‐methyl‐4‐(2,3‐dichlorophenyl)‐3,5‐pyridinedicarboxylate Coupled to a 1‐Methyl‐1,4‐dihydropyridyl‐3‐carbonyl Chemical Delivery System
Author(s) -
Yiu Saihay,
Knaus Edward E.
Publication year - 1999
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/(sici)1521-4184(199910)332:10<363::aid-ardp363>3.0.co;2-t
Subject(s) - nimodipine , chemistry , felodipine , bioisostere , antagonist , stereochemistry , anticonvulsant , calcium channel , dihydropyridine , nitrendipine , chemical synthesis , calcium , biochemistry , in vitro , organic chemistry , receptor , medicine , blood pressure , epilepsy , radiology , neuroscience , biology
3‐Ethyl 5‐methyl 1,4‐dihydro‐2‐[(2‐hydroxyethoxy)methyl]‐6‐methyl‐4‐(2,3‐dichlorophenyl)‐3,5‐pyridinedicarboxylate ( 13 ), a bioisostere of amlodipine, was prepared by the reaction of ethyl 4‐(2‐hydroxyethoxy)acetoacetate ( 11 ) with methyl 2‐(2,3‐dichlorobenzylidene) acetoacetate ( 12 ) and NH 4 OAc. Compound 13 was elaborated to the target product 3‐ethyl 5‐methyl 1,4‐dihydro‐2‐[2‐[(1‐methyl‐1,4‐dihydropyridyl‐3‐carbonyloxy)ethoxy]methyl]‐6‐methyl‐4‐(2,3‐dichlorophenyl)‐3,5‐pyridinedicarboxylate ( 16 ). The C‐2 CH 2 OCH 2 CH 2 OH compound ( 13 , IC 50 = 6.56 × 10 ‐9 M) was about 44‐fold more active as a calcium channel antagonist than the reference drug nimodipine (IC 50 = 1.49 × 10 ‐8 M), but 4‐fold less potent than felodipine (IC 50 = 1.45 × 10 ‐9 M). Compound 16 , possessing the 1‐methyl‐3‐pyridylcarbonyloxy chemical delivery system moiety is a slightly less potent calcium channel antagonist (IC 50 = 2.99 × 10 ‐8 M) than the parent compound 13 . Compounds 13, 16, felodipine and nimodipine are highly lipophilic (Kp = 227, 344, 442 and 187, respectively). The C‐2 CH 2 OCH 2 CH 2 OH compound ( 13 ) exhibited equipotent anticonvulsant activity to nimodipine in the maximal electroshock (MES) anticonvulsant screen. Unlike nimodipine, 13 provided modest protection in the subcutaneous metrazol (scMet) anticonvulsant screen. In contrast, compound 16 was inactive in both the MES and scMet screens.