1. Discovery and Clinical Evaluation of MK‐8150, A Novel Nitric Oxide Donor With a Unique Mechanism of Nitric Oxide Release
by Clayton D. Knox, Pieter‐Jan de Kam, Karim Azer, Peggy Wong, Antwan G. Ederveen, Diane Shevell, Christopher Morabito, Alan G. Meehan, Wen Liu, Tom Reynders, Jean Francois Denef, Anna Mitselos, Daniel Jonathan, David E. Gutstein, Kaushik Mitra, Shu Yu Sun, Michael Man‐Chu Lo, Doris Cully, and Amjad Ali
J Am Heart Assoc
Volume 5(9):e003493
August 25, 2016
© 2016 Clayton D. Knox et al.

2. Chemical structures of MK‐8150 and Compound 2.
Clayton D. Knox et al. J Am Heart Assoc 2016;5:e003493
© 2016 Clayton D. Knox et al.

3. Effect of Compound 2 on cGMP in human primary renal proximal epithelial tubule cells.
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.
Clayton D. Knox et al. J Am Heart Assoc 2016;5:e003493
© 2016 Clayton D. Knox et al.

4. 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...
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‐ or 3 mg/kg. *P<0.05, compared to vehicle control; #P<0.05, compared to 1 mg/kg.
Clayton D. Knox et al. J Am Heart Assoc 2016;5:e003493
© 2016 Clayton D. Knox et al.

5. 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.
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.
Clayton D. Knox et al. J Am Heart Assoc 2016;5:e003493
© 2016 Clayton D. Knox et al.

6. 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.
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‐ ‐mg group. B, n=6 each for MK‐8150 5‐, 10‐, 15‐, and 20‐mg groups. HR indicates heart rate.
Clayton D. Knox et al. J Am Heart Assoc 2016;5:e003493
© 2016 Clayton D. Knox et al.

7. 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 hype...
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‐ ‐mg groups; n=5 for MK‐8150 5‐ and 24‐mg groups.
Clayton D. Knox et al. J Am Heart Assoc 2016;5:e003493
© 2016 Clayton D. Knox et al.

8. 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 ...
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.
Clayton D. Knox et al. J Am Heart Assoc 2016;5:e003493
© 2016 Clayton D. Knox et al.

9. 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‐do...
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‐  mg QD on Days 1 to 7 followed by MK‐  mg QD on Days 8 to 28; n=6 patients on placebo. *P<0.05, compared to placebo.
Clayton D. Knox et al. J Am Heart Assoc 2016;5:e003493
© 2016 Clayton D. Knox et al.