LONG-ACTING DIHYDROPYRIDINE CALCIUM-ANTAGONISTS .8. A COMPARISON OF THE PHARMACOLOGICAL AND PHARMACOKINETIC PROPERTIES OF AMLODIPINE WITH ITS CARBA AND THIO-BIOISOSTERES

In order to evaluate the contribution to the overall pharmacokinetic and pharmacological profile of amlodipine made by the side-chain ether oxygen atom and the intramolecular hydrogen bond to the DHP ring NH proton, the profile of amlodipine was compared with that of its carba and thio bioisosteres. Replacing the side-chain oxygen by carbon dramatically reduces in vitro calcium antagonist potency, an effect which may be attributed to the loss of a through-bond inductive effect on the DHP ring NH proton, while both the thio and carba analogues show lower in vitro selectivity than amlodipine for vascular over cardiac tissue. On intravenous administration to anaesthetised dogs, compounds 2 and 3 both exhibit marked depression of myocardial contractility at doses equal or close to their ED50 for reduction of coronary vascular resistance. The plasma clearances of amlodipine and analogues 3 and 4 are similar, suggesting that the conformation adopted by the 2-sidechain has little influence on this parameter although bulk and polarity are important. However, compounds 3 and 4 have markedly lower volumes of distribution (6 and 8 dm3 kg-1, respectively) than amlodipine (25 dm3 kg-1) and consequently shorter half-lives; this may be a consequence of their inability to form an intramolecular hydrogen bond.