Drug approval-date Target In vitro studies In vivo studies Reference
Sacubitril/Valsartan Sodium Hydrate
2015
AT1; NEP Recombinant protein, NEP and NEP-2 enzyme activity assay. Rat cardiac fibroblasts, anti-fibrotic effects. Rat cardiomyocytes, anti-hypertrophic effect. Rat and human renal cortex tissue, NEP activity. Conscious rats, effect on ANP potentiation; evaluation of changes of markers both the RAAS and the NP system; Bradykinin action. Conscious dogs, effect on ANP potentiation; evaluation of changes of markers of both the RAAS and the NP system; cGMP. SHRSP, effect on vascular remodeling and cardiac fibrosis, cardiac arteriole size, collagen deposltion, and MMP-2 activity. Dahl Salt-Sensitive rat, effect on left-ventricular weight; diuresis and natriuresis; blood pressure; renal function; urinary cGMP. MI rat models, Cardiac remodeling. Double-transgenic rat, effect on blood pressure. DOCA rat, effect on blood pressure. SHR, effect on blood pressure.
FDA reviews: 207620Orig1s000
Macitentan
2013
Tissue-targeting dual endothelin receptor
ETA and ETB, receptors stably expressed CHO cell, binding assays; effect on intracellular calcium. Isolated rat aorta and trachea, inhibition of ET-1- induced contraction in isolated tissues. Pulmonary arterial smooth muscle cells, inhibitory potency and dissociation kinetics. Normal rats, ET-1 plasma concentrations; Hemodynamic effects. Guinea pigs, effects on electrocardiogram intervals. Conscious dogs, electrocardiogram intervals and arterial blood pressure. Dahl salt-sensitive rats, effects on mean arterial blood pressure and heart rate. Deoxycorticosterone acetate (DOCA)-salt rats, effects on blood pressure and heart rate. Monocrotaline induced pulmonary hypertension in conscious wistar rats, effect on mean pulmonary arterial pressure; and on the development of pulmonary arterial wall thickness, right ventricular hypertrophy and survival. Rat model of bleomycin-induced pulmonary hypertension and fibrosis, effect on right ventricular hypertrophy.
FDA reviews: 204410Orig1s000
Tolvaptan
2009
V2R
Human endocervical carcinoma cell line (Hela cells) expressing human AVP receptor subtypes, antagonistic effects. Hela cells expressing human AVP V2-receptor, antagonistic effects. Water-loaded, alcohol-anesthetized rats, evaluation of the inhibitory effect of V2-receptor antagonist tolvaptan on AVP-induced antidiuresis. Health animals Aquaretic effect of orally administered tolvaptan was investigated in conscious B6C3F1 mice, SD rats, and New Zealand white rabbits. Tolvaptan increased urine volume and decreased urine osmolality.
Aquaretic effect of tolvaptan was examined on serum AVP, pituitary AVP and the number of AVP receptors in the liver and in the kidney in male SD rats. Animal model of HF Conscious, pacing-induced HF model of dogs, aquaretic effect. Rat acute and chronic models of hyponatremia, effects on hyponatremia.
FDA reviews: NDA 22-275
Ivabradine Hydrochloride
2005
HCN channels
Rat isolated atria and aorta, effect on the spontaneous beating rate; Spontaneous firing rate (action potentials per min). Rabbit isolated sinoatrial node tissue / cell, Spontaneous firing rate (action potentials per min); electrical activity; hyperpolarization-activated (If), delayed-rectifier potassium (IK), T- and L-type calcium (ICa,L and ICa,T). Human atrial myocyte, If current. HCN channel isoforms expressed in HEK293 cells, effect on HCN1 and HCN4 channels including voltage or currentdependency, reversibility of the interaction, interaction with open and/or closed channel. Conscious normotensive rat, Bradycardic effect. Conscious Long Evans rats, Cardiac and regional haemodynamic effects, including heart rate, mean blood pressure, cardiac index, Stroke index, Peak aortic flow, dF/dtmaz, Total peripheral conductance, Central venous pressure. Anesthetized pigs, Hemodynamic and electrocardiographic effects, The effects on heart rate, LVdP/dt, cardiac output, stroke volume and total peripheral resistance. Rat model of left ventricular dysfunction and chronic HF, myocardial infarction was induced by left coronary artery ligation. Dog CHF model, intracoronary microembolizations, left ventricular end systolic volume, left ventricular ejection fraction. 132-AR transgenic mice, effect on survival and on the development of HF. Rats pressure overload-induced HF in, aortic banding. Murine transgenic model, cardiac over-expression of β2-adrenergic receptors.
FDA reviews: 206143Orig1s000