Discovery and Clinical Evaluation of MK-8150, A Novel Nitric Oxide Donor With a Unique Mechanism of Nitric Oxide Release

Abstract

Background: Nitric oxide donors are widely used to treat cardiovascular disease, but their major limitation is the development of tolerance, a multifactorial process to which the in vivo release of nitric oxide is thought to contribute. Here we describe the preclinical and clinical results of a translational drug development effort to create a next-generation nitric oxide donor with improved pharmacokinetic properties and a unique mechanism of nitric oxide release through CYP3A4 metabolism that was designed to circumvent the development of tolerance.

Methods and results: Single- and multiple-dose studies in telemetered dogs showed that MK-8150 induced robust blood-pressure lowering that was sustained over 14 days. The molecule was safe and well tolerated in humans, and single doses reduced systolic blood pressure by 5 to 20 mm Hg in hypertensive patients. Multiple-dose studies in hypertensive patients showed that the blood-pressure-lowering effect diminished after 10 days, and 28-day studies showed that the hemodynamic effects were completely lost by day 28, even when the dose of MK-8150 was increased during the dosing period.

Conclusions: The novel nitric oxide donor MK-8150 induced significant blood-pressure lowering in dogs and humans for up to 14 days. However, despite a unique mechanism of nitric oxide release mediated by CYP3A4 metabolism, tolerance developed over 28 days, suggesting that tolerance to nitric oxide donors is multifactorial and cannot be overcome solely through altered in vivo release of nitric oxide.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01590810 and NCT01656408.

Keywords: blood pressure; nitrate; nitrate tolerance; nitric oxide; vasodilation.

© 2016 The Authors and Merck & Co., Inc. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1

Chemical structures of MK‐8150 and Compound 2.

Figure 2

Effect of Compound 2 on cGMP in human primary renal proximal epithelial tubule cells. A, Effect of Compound 2 compared with DMSO vehicle on intracellular cGMP over time. B, Effect of Compound 2 compared with DMSO vehicle on secreted cGMP over time. C, Relationship between Compound 2 concentration and intracellular cGMP level. Values are expressed as group means±SE. DMSO indicates dimethyl sulfoxide.

Figure 3

Eighteen‐hour time‐weighted average of change from baseline in systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), pulse pressure (PP), and heart rate (HR) in 6 dogs treated with a single dose of vehicle or MK‐8150 1 or 3 mg/kg. *P<0.05, compared to vehicle control; #P<0.05, compared to 1 mg/kg.

Figure 4

Daily average of change from baseline in heart rate (HR), diastolic blood pressure (DBP), and systolic blood pressure (SBP) in 6 dogs treated with daily doses of MK‐8150 3 mg/kg for 14 days. There were no changes from baseline in these parameters in vehicle‐treated animals (data not shown). Values are 18‐hour time‐weighted average expressed as group mean±SEM. *P<0.05, compared to baseline.

Figure 5

Mean plasma concentration‐time plots for MK‐8150 in (A) a single‐ascending‐dose study in healthy male volunteers and hypertensive male patients and (B) a multiple‐dose study in hypertensive male patients. A, n=6 for MK‐8150 2‐, 4‐, 6‐, 12‐, 24‐, 45‐, and 90‐mg groups; n=5 for MK‐8150 120‐mg group. B, n=6 each for MK‐8150 5‐, 10‐, 15‐, and 20‐mg groups. HR indicates heart rate.

Figure 6

Mean±SE change from baseline in (A) peripheral systolic blood pressure (pSBP; mm Hg) and (B) peripheral diastolic blood pressure (pDBP; mm Hg) over 24 hours following single‐dose administration of placebo (PBO) and MK‐8150 5, 24, and 90 mg in hypertensive male patients. n=6 for PBO and MK‐8150 90‐mg groups; n=5 for MK‐8150 5‐ and 24‐mg groups.

Figure 7

Mean±SE peripheral systolic (pSBP) and diastolic (pDBP) blood pressure (time‐weighted average [TWA]0‐24h, mm Hg) at day 1 and day 10 for MK‐8150 5, 10, 15, and 20 mg in hypertensive male patients participating in a 10‐day multiple‐dose study. n=2 for placebo (0 mg) group; n=6 each for MK‐8150 5‐, 10‐, 15‐, and 20‐mg groups. *P<0.05, compared to placebo.

Figure 8

Mean±SE MK‐8150 exposure (AUC0‐24 [μmol/L×hour]) and placebo‐adjusted change from baseline in peripheral systolic (pSBP) and diastolic (pDBP) blood pressure over time in hypertensive male patients participating in Panel 9 of the 28‐day multiple‐dose study. n=12 patients on MK‐8150 10 mg QD on Days 1 to 7 followed by MK‐8150 20 mg QD on Days 8 to 28; n=6 patients on placebo. *P<0.05, compared to placebo.