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

Abstract

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.

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–5

“…Pettersen et al report the discovery and optimization of a series of novel inhibitors of 5-lipooxygenase-activating protein, which stimulates the production of leukotrienes, important mediators in the pathogenesis and progression of atherosclerosis [2]. In particular, compound AZD5718, (1 R ,2 R )-2-{4-[3-methyl-1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazol-5-yl]benzoyl}- N -(4-oxo-4,5,6,7-tetrahydropyrazolo-[1,5- a ]pyrazin-3-yl)cyclohexanecarboxamide, demonstrated a favorable pharmacokinetic and safety profile in rats and dogs [3]. This led to phase-I studies in healthy subjects, which showed a strong relationship between plasma concentrations of AZD5718 and inhibition of both leukotriene B4, involved in inflammation, and leukotriene E4, a cysteinyl leukotriene also involved in inflammation [3].…”

Phase 1 Pharmacokinetic Study of AZD5718 in Healthy Volunteers: Effects of Coadministration With Rosuvastatin, Formulation and Food on Oral Bioavailability

“…Structure of AZD5718 ((1 R ,2 R )‐2‐{4‐[3‐Methyl‐1‐(tetrahydro‐2 H ‐pyran‐2‐yl)‐1 H ‐pyrazol‐5‐yl]benzoyl}‐N‐(4‐oxo‐4,5,6,7‐tetrahydropyrazolo[1,5‐ a ]pyrazin‐3‐yl)cyclohexanecarboxamide) …”

“…In vitro studies indicate that cytochrome P450 (CYP) 3A4 and CYP3A5 are involved in the metabolism of AZD5718, with glucuronidation by uridine 5’‐diphosphate glucuronosyltransferases 1A1, 1A3, and 1A4 also contributing to metabolism . AZD5718 does not inhibit CYP isoforms 1A2, 2C8, 2C9, 2C19, 2D6, or 3A4 (IC 50 > 20 µM) or P‐glycoprotein (IC 50 > 100 µmol/L).…”

“…In vitro studies indicate that cytochrome P450 (CYP) 3A4 and CYP3A5 are involved in the metabolism of AZD5718, with glucuronidation by uridine 5’‐diphosphate glucuronosyltransferases 1A1, 1A3, and 1A4 also contributing to metabolism . AZD5718 does not inhibit CYP isoforms 1A2, 2C8, 2C9, 2C19, 2D6, or 3A4 (IC 50 > 20 µM) or P‐glycoprotein (IC 50 > 100 µmol/L). Together with the almost complete inhibition of leukotriene B 4 and E 4 production in healthy volunteers in the low nanomolar range, in vitro profiling of AZD5718 indicates low risk of drug‐drug interactions with AZD5718 via CYP450 inhibition or induction or at the transporter level.…”

“…11 Second, certain haplotypes of the gene encoding FLAP (ALOX5AP) are associated with increased risk of myocardial infarction. 12 16 Third, the 5-lipoxygenase inhibitor VIA-2291 reduced leukotriene B 4 production, lowered noncalcified plaque volume, and prevented the appearance of new coronary lesions in patients with acute coronary syndrome in a phase 2 clinical trial. 13 VIA-2291 also dosedependently improved left ventricular ejection fraction in patients with acute coronary syndrome.…”