Discovery and Early Clinical Development of an Inhibitor of 5-Lipoxygenase Activating Protein (AZD5718) for Treatment of Coronary Artery Disease.

5-Lipoxygenase activating protein (FLAP) inhibitors attenuate 5-lipoxygenase pathway activity and reduce the production of proinflammatory and vasoactive leukotrienes. As such, they are hypothesized to have therapeutic benefit for the treatment of diseases that involve chronic inflammation including coronary artery disease. Herein, we disclose the medicinal chemistry discovery and the early clinical development of the FLAP inhibitor AZD5718 (12). Multiparameter optimization included securing adequate potency in human whole blood, navigation away from Ames mutagenic amine fragments while balancing metabolic stability and PK properties allowing for clinically relevant exposures after oral dosing. The superior safety profile of AZD5718 compared to earlier frontrunner compounds allowed us to perform a phase 1 clinical study in which AZD5718 demonstrated a dose dependent and greater than 90% suppression of leukotriene production over 24 h. Currently, AZD5718 is evaluated in a phase 2a study for treatment of coronary artery disease.

Pharmacodynamic, pharmacokinetic and clinical effects of clevidipine, an ultrashort-acting calcium antagonist for rapid blood pressure control.

Clevidipine is an ultrashort-acting vasoselective calcium antagonist under development for short-term intravenous control of blood pressure. Studies in animals, healthy volunteers and patients have demonstrated the vascular selectivity and rapid onset and offset of antihypertensive action of clevidipine, a synthetic 1,4-dihydropyridine that inhibits L-type calcium channels. Clevidipine has a high clearance (0.05 L/min/kg) and is rapidly hydrolyzed to inactive metabolites by esterases in arterial blood. Its half-life in patients undergoing cardiac surgery is less than one min. Unlike sodium nitroprusside, a drug commonly used for the short-term control of blood pressure, which dilates both arterioles and veins, clevidipine reduces blood pressure through a selective effect on arterioles. As documented in animals and in cardiac surgical patients, clevidipine reduces peripheral resistance without any undesirable effect on cardiac filling pressure. It increases stroke volume and cardiac output. In anesthetized patients undergoing cardiac surgery clevidipine, unlike sodium nitroprusside, does not increase heart rate. In addition of having a favorable hemodynamic profile, suitable for rapid control of blood pressure, clevidipine protects against ischemia/reperfusion injuries, which are not uncommon during major surgery. In anesthetized pigs, clevidipine reduced infarct size after 45 min-long myocardial ischemia by 40%. In rats, renal function and splanchnic blood flow were better maintained when blood pressure was reduced with clevidipine than with sodium nitroprusside. Clevidipine was well tolerated in Phases I and II of clinical trials that included more than 300 individuals/patients. Since there are no known compounds with similar pharmacodynamic and pharmacokinetic properties in clinical development, it is anticipated that clevidipine, a compound tailored to the needs of anesthesiologists, has the potential to become a drug of choice for controlling blood pressure during surgical procedures.

Time-dependent cardioprotection with calcium antagonism and experimental studies with clevidipine in ischemic-reperfused pig hearts: part I.

Clevidipine is a new ultrashort-acting dihydropyridine calcium antagonist developed for blood pressure regulation during cardiac surgery. When given locally to the ischemic and reperfused myocardium, clevidipine exerts a cardioprotective effect that varies depending on the timing of administration during ischemia. The current study explored the pharmacokinetics of clevidipine when administered locally into the coronary circulation. Pentobarbital-anesthetized pigs were randomly divided into four groups, of which three were subjected to myocardial ischemia through ligation of the left anterior descending coronary artery (LAD) for 15, 35, or 45 minutes (n = 4 in each group). The fourth group (n = 4) was not subjected to LAD occlusion and acted as nonischemic controls. Clevidipine (0.3 nmol/kg per minute) was infused over a period of 5 minutes through a catheter distal to the LAD ligation in the ischemic pigs, or at the corresponding site of the nonligated LAD in the nonischemic pigs. Following release of the LAD ligation, or in the nonligated group following the drug infusion, the pigs were subjected to 60 minutes of reperfusion. Simultaneous blood samples were obtained for analysis of clevidipine from the femoral artery and the coronary vein during reperfusion and during drug infusion in the nonischemic pigs. Blood samples for estimating the in vitro hydrolysis rate both in whole blood and in plasma were also obtained. In nonischemic hearts, clevidipine reached a steady state level in the coronary venous blood of about 30 nM during the infusion. The concentration declined almost to the detection limit (1 nM) within 3 minutes of the end of infusion. The mean blood clearance of clevidipine was calculated to be 0.17 l/min per kilogram, and the estimated half-life was 0.5 minute. In animals subjected to different periods of ischemia, very low levels of clevidipine were detected in the coronary venous blood only during the first 2 minutes of reperfusion. There were no detectable levels in the arterial blood at any time. Blood concentration profiles of clevidipine did not differ with the length of myocardial ischemia. The in vitro half-life in pig blood was 13 minutes, and the corresponding half-life in plasma was 111 minutes. At a dose known to exert cardioprotection when given as an intracoronary injection, the systemic concentration of clevidipine does not reach pharmacologically active levels. Clevidipine has an ultrashort blood half-life, and ischemic duration of up to 45 minutes does not seem to change the cardiac metabolism of this drug. Thus, it represents a pharmacological tool well suited for the study of time windows in cardioprotection. Moreover, considering the possibility of exerting myocardioprotection without any systemic effects, it could be an interesting compound to test in a clinical setting.