Candesartan cilexetil: Development and preclinical studies

The nonpeptide AT(1) receptor antagonist candesartan is generated from the prodrug candesartan cilexetil during gastrointestinal absorption. In vitro studies have shown that candesartan acts as an insurmountable, tightly bound antagonist at the AT(1) receptor, producing a dose-dependent reduction in the maximal responses to angiotensin II (AII) and virtually an elimination of the AT(1) receptor-mediated effects of AII at high concentrations. The binding of candesartan to the AT(1) receptor is highly selective, and the drug dissociates slowly from the receptor. Candesartan cilexetil produces the expected changes in the parameters of the renin-angiotensin system. Plasma renin activity and plasma AII concentrations were increased and aldosterone levels decreased following drug application. As a consequence, stimulation of AT(2) receptor-mediated actions of AII, such as growth inhibition and vasodilation, may contribute to the overall effects of the AT(1) antagonist, since the AT(2) receptors are left unopposed by candesartan. The antihypertensive efficacy of candesartan cilexetil has been demonstrated in different animal models of hypertension including 2 kidney-1 clip and 1 kidney-1 clip hypertensive rats and spontaneously hypertensive rats (SHR). Candesartan cilexetil produced a slow onset, long-lasting antihypertensive action at a dose range of 0.1-10 mg/kg with no rebound effect upon drug withdrawal. A growing number of studies indicate that candesartan cilexetil can produce end organ protection in addition to lowering blood pressure. In preclinical studies, candesartan cilexetil caused prevention and regression of left ventricular hypertrophy and cardiac fibrosis, protected the heart against ischemia-reperfusion injury and reduced myocardial damage during myocarditis. In different animal models of renal dysfunction, candesartan cilexetil reduced proteinuria and albuminuria, inhibited histopathological renal changes and controlled the renal expression of TGF-beta1 and collagen types I and III. Finally, in stroke prone SHR, candesartan cilexetil markedly attenuated the incidence of stroke even at low doses, with minimal blood pressure lowering effects, and fully protected against stroke at higher doses.