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Synthesis of alkyl 6‐methyl‐4‐(2‐pyridyl)‐1,2,3,4‐tetrahydro‐2 H ‐pyrimidine‐2‐one‐5‐carboxylates for evaluation as calcium channel antagonists
Author(s) -
Kaur Kuljeet,
Knaus Edward E.
Publication year - 2007
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570440339
Subject(s) - chemistry , alkyl , nifedipine , antagonist , pyrimidine , stereochemistry , calcium channel , calcium , guinea pig , medicinal chemistry , medicine , biochemistry , receptor , organic chemistry
The Bigenelli acid catalyzed condensation of 2‐pyridylcarboxaldehyde ( 1 ), urea ( 2 ) and an alkyl acetoacetate ( 3 ) afforded the respective alkyl (Me, Et, i ‐Pr, i ‐Bu, t ‐Bu) 6‐methyl‐4‐(2‐pyridyl)‐1,2,3,4‐tetrahydro‐2 H ‐pyrimidine‐2‐one‐5‐carboxylates ( 4a‐e ). The most potent calcium channel antagonist ethyl 6‐methyl‐4‐(2‐pyridyl)‐1,2,3,4‐tetrahydro‐2 H ‐pyrimidine‐2‐one‐5‐carboxylate ( 4b , IC 50 = 1.67 × 10 −5 M) wasa much weaker calcium channel antagonist than the reference drug nifedipine (Adalat®, IC 50 = 1.40 × 10 −8 M) on guinea pig ileal longitudinal smooth muscle (GPILSM). The alkyl 6‐methyl‐4‐(2‐pyridyl)‐1,2,3,4‐tetrahydro‐2 H ‐pyrimidine‐2‐one‐5‐carboxylates did not show any inotropic effect on heart since no increase, or decrease, in the contractile force of guinea pig left atrium was observed. These structure activity studies show that the alkyl 6‐methyl‐4‐(2‐pyridyl)‐1,2,3,4‐tetrahydro‐2 H ‐pyrimidine‐2‐one‐5‐carboxylates ( 4a‐e ) are partial bioisosteres of nifedipine with respect to calcium channel antagonist activity on guinea pig ileal longitudinal smooth muscle (GPILSM).