The 1,4-dihydropyridines are the best studied Ca
2+ channel antagonists. A number of
analogs within this series have been developed: amlodipine (7.40), felodipine (7.41),
isradipine (7.42), nicardipine (7.43), nifedipine (7.38), nimodipine (7.37), nitrendipine
(7.44), and nisoldipine (7.45). From a pharmacokinetic perspective, these agents vary
widely: nisoldipine has only 5% oral bioavailability, whereas amlodipine has 80–90%
oral bioavailability; nimodipine has an elimination half-life of 1–2 hours whereas
amlodipine’s half-life is 40–50 hours. The 1,4-DHPs, in general, undergo extensive
first-pass metabolism; in many cases, the dihydropyridine ring is initially oxidized to a
pyridine analog. Pharmacodynamically, the 1,4-DHPs bind to the α-1 subunit of the
L-type Ca
2+ channel protein. This protein readily changes shape in response to the transmembrane voltage gradient and exists in three primary conformations: “resting” (can be
stimulated to open by a membrane depolarization), “open” (permitting Ca
2+ to enter),
and “inactive” (temporarily refractory to depolarization-induced opening). 1,4-DHPs
preferentially bind to the L-type channel protein when it is in either the “open” or the
“inactive” conformation; such conformation-dependent binding is referred to as “usedependent binding.” Due to allosteric interactions between receptors, verapamil inhibits
the binding of 1,4-DHPs to the Ca
2+ channel, whereas diltiazem enhances 1,4-DHP
binding.
These various pharmacokinetic and pharmacodynamic properties have enabled the
identification of four basic structure–activity rules for the 1,4-DHP antagonists:
1. The 1,4-DHP ring is essential for bioactivity; the use of reduced (pyridine) or oxidized (piperidine) ring systems reduces activity; substitution at the N1 position
reduces activity
2. Ester groups at the C3 and C5 positions optimize activity; when the C3 and C5 esters
are nonidentical, the C4 carbon becomes chiral; such asymmetrical compounds
exhibit enhanced selectivity for specific blood vessels
428
MEDICINAL CHEMISTRY
2+ channel antagonists. A number of
analogs within this series have been developed: amlodipine (7.40), felodipine (7.41),
isradipine (7.42), nicardipine (7.43), nifedipine (7.38), nimodipine (7.37), nitrendipine
(7.44), and nisoldipine (7.45). From a pharmacokinetic perspective, these agents vary
widely: nisoldipine has only 5% oral bioavailability, whereas amlodipine has 80–90%
oral bioavailability; nimodipine has an elimination half-life of 1–2 hours whereas
amlodipine’s half-life is 40–50 hours. The 1,4-DHPs, in general, undergo extensive
first-pass metabolism; in many cases, the dihydropyridine ring is initially oxidized to a
pyridine analog. Pharmacodynamically, the 1,4-DHPs bind to the α-1 subunit of the
L-type Ca
2+ channel protein. This protein readily changes shape in response to the transmembrane voltage gradient and exists in three primary conformations: “resting” (can be
stimulated to open by a membrane depolarization), “open” (permitting Ca
2+ to enter),
and “inactive” (temporarily refractory to depolarization-induced opening). 1,4-DHPs
preferentially bind to the L-type channel protein when it is in either the “open” or the
“inactive” conformation; such conformation-dependent binding is referred to as “usedependent binding.” Due to allosteric interactions between receptors, verapamil inhibits
the binding of 1,4-DHPs to the Ca
2+ channel, whereas diltiazem enhances 1,4-DHP
binding.
These various pharmacokinetic and pharmacodynamic properties have enabled the
identification of four basic structure–activity rules for the 1,4-DHP antagonists:
1. The 1,4-DHP ring is essential for bioactivity; the use of reduced (pyridine) or oxidized (piperidine) ring systems reduces activity; substitution at the N1 position
reduces activity
2. Ester groups at the C3 and C5 positions optimize activity; when the C3 and C5 esters
are nonidentical, the C4 carbon becomes chiral; such asymmetrical compounds
exhibit enhanced selectivity for specific blood vessels
428
MEDICINAL CHEMISTRY