The aspartic proteinase renin is an attractive target for the treatment of hypertension and cardiovascular/renal disease such as chronic kidney disease and heart failure. We introduced an S1′ site binder into the lead compound 1 guided by structure-based drug design (SBDD), and further optimization of physicochemical properties led to the discovery of benzimidazole derivative 10 (1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-yl)carbonylpiperidin-3-yl]-1H-benzimidazole-2-carboxamide hydrochloride, TAK-272) as a highly potent and orally active renin inhibitor. Compound 10 demonstrated good oral bioavailability (BA) and long-lasting efficacy in rats. Compound 10 is currently in clinical trials.

The renin-angiotensin system (RAS), which plays an important role in the progression of heart failure, is efficiently blocked by the inhibition of renin, the rate-limiting enzyme in the RAS cascade. In the present study, we investigated the cardioprotective effects of TAK-272 (SCO-272, imarikiren), a novel, orally effective direct renin inhibitor (DRI), and compared its efficacy with that of aliskiren, a DRI that is already available in the market. TAK-272 was administered to calsequestrin transgenic (CSQ-tg) heart failure mouse model that show severe symptoms and high mortality. The CSQ-tg mice treated with 300 mg/kg, the highest dose tested, of TAK-272 showed significantly reduced plasma renin activity (PRA), cardiac hypertrophy, and lung congestion. Further, TAK-272 reduced cardiomyocyte injury accompanied by an attenuation of the increase in NADPH oxidase 4 and nitric oxide synthase 3 expressions. TAK-272 also prolonged the survival of CSQ-tg mice in a dose-dependent manner (30 mg/kg: P = 0.42, 100 mg/kg: P = 0.12, 300 mg/kg: P < 0.01). Additionally, when compared at the same dose level (300 mg/kg), TAK-272 showed strong and sustained PRA inhibition and reduced the heart weight and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration, a heart failure biomarker, while aliskiren showed a significant weaker PRA inhibition and failed to demonstrate any cardioprotective effects. Our results showed that TAK-272 is an orally active and persistent renin inhibitor, which reduced the mortality of CSQ-tg mice and conferred protection against cardiac hypertrophy and injury. Thus, TAK-272 treatment could provide a new therapeutic approach for heart failure.

The action of the aspartyl protease renin is the rate-limiting initial step of the renin-angiotensin-aldosterone system. Therefore, renin is a particularly promising target for blood pressure as well as onset and progression of cardiovascular and renal diseases. New pyrimidine derivatives 5-14 were designed in an attempt to enhance the renin inhibitory activity of compound 3 identified by our previous fragment-based drug design approach. Introduction of a basic amine essential for interaction with the two aspartic acids in the catalytic site and optimization of the S1/S3 binding elements including an induced-fit structural change of Leu114 ('Leu-in' to 'Leu-out') by a rational structure-based drug design approach led to the discovery of N-(piperidin-3-yl)pyrimidine-5-carboxamide 14, a 65,000-fold more potent renin inhibitor than compound 3. Surprisingly, this remarkable enhancement in the inhibitory activity of compound 14 has been achieved by the overall addition of only seven heavy atoms to compound 3. Compound 14 demonstrated excellent selectivity over other aspartyl proteases and moderate oral bioavailability in rats.

The antihypertensive effects of an angiotensin II antagonist, candesartan cilexetil (TCV-116), and other classes of antihypertensive drugs (including a calcium antagonist, manidipine; a diuretic, hydrochlorothiazide (HCTZ); an alpha-blocker, prazosin; and a beta-blocker, atenolol) administered in combination were examined in spontaneously hypertensive rats by oral administration daily for 2 wk. TCV-116 at 1 mg/kg lowered the blood pressure by about 50 and 30 mmHg, 5 and 24 h after dosing, respectively. The blood pressure was slightly lowered by HCTZ at 10 mg/kg, but it was synergistically reduced when HCTZ was given in combination with TCV-116. Manidipine at 3 mg/kg lowered the blood pressure by about 50 mmHg 1 h after administration. When manidipine was given in combination with TCV-116, blood pressure was reduced additively. Prazosin at 1 mg/kg lowered the blood pressure by 40 to 50 mmHg 1 h after dosing. When prazosin was given in combination with TCV-116, the reduction was intensified more than additively, to about 100 mmHg. Atenolol at 50 mg/kg lowered the blood pressure by 10 to 20 mmHg 5 h after dosing. Even when atenolol was administered in combination with TCV-116, the reduction in blood pressure was virtually the same as that observed when TCV-116 was given alone. TCV-116 and HCTZ had no effect on the pulse rate, whereas manidipine and prazosin both increased it, owing to reflex tachycardia, and atenolol decreased it. TCV-116 had no effect on the change in the pulse rate induced by these antihypertensive drugs and no effect on HCTZ-induced diuresis. TCV-116 and HCTZ each caused a significant increase in plasma renin concentration (PRC), and prazosin caused a slight elevation. Manidipine had no effect on the PRC, whereas atenolol reduced it. Given in combination with TCV-116, these antihypertensive drugs had the same effect on the elevated PRC induced by TCV-116 as they did on the basal PRC when administered alone. These results suggest that antihypertensive drugs that cause compensatory activation of the renin-angiotensin system have more marked antihypertensive activity when given in combination with TCV-116, but that there will is no combined effect on the pulse rate.

ABSTRACT-The regional hemodynamic effects of candesartan cilexetil (TCV-116), a selective angiotensin II AT,-receptor antagonist, and enalapril, an angiotensin-converting enzyme inhibitor, were compared in conscious spontaneously hypertensive rats (SHR). A 7-day repeated administration study was carried out. TCV-116 (1 mg/kg, p.o.) and enalapril (10 mg/kg, p.o.) reduced blood pressure to the same extent 5 hr after administration on the 1st and the 7th day. At these points, the cardiac index and organ or tissue blood flow were measured by the non-radioactive colored dye-extraction microsphere technique. Repeated administration of TCV-116, and single and repeated administration of enalapril significantly increased renal blood flow without any changes in the cardiac index. TCV-116 and enalapril also tended to increase splanchnic blood flow following the 1st dose but not the 7th dose. No significant changes in blood flow were observed in the brain, heart, adrenal, skin and skeletal muscle. These results suggest that the anti hypertensive effects of TCV-116 and enalapril are attributable to the systemic reduction of vascular resist ance caused by the dilatation of blood vessels. These hemodynamic effects of TCV-116, like those of enalapril, may be beneficial in the treatment of hypertension.