title: Discovery and Clinical Evaluation of MK-8150, A Novel Nitric Oxide Donor With a Unique Mechanism of Nitric Oxide Release.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01590810 and NCT01656408.
authors: Merck & Co, Inc, Kenilworth, NJ.
authors: Clayton D
authors: CD
authors: Knox
authors: Merck & Co, Inc, Kenilworth, NJ.
authors: Pieter-Jan
authors: PJ
authors: de Kam
authors: Merck & Co, Inc, Kenilworth, NJ.
authors: Karim
authors: K
authors: Azer
authors: Merck & Co, Inc, Kenilworth, NJ.
authors: Peggy
authors: P
authors: Wong
authors: Merck & Co, Inc, Kenilworth, NJ.
authors: Antwan G
authors: AG
authors: Ederveen
authors: Merck & Co, Inc, Kenilworth, NJ.
authors: Diane
authors: D
authors: Shevell
authors: Merck & Co, Inc, Kenilworth, NJ.
authors: Christopher
authors: C
authors: Morabito
authors: Merck & Co, Inc, Kenilworth, NJ.
authors: Alan G
authors: AG
authors: Meehan
authors: Merck & Co, Inc, Kenilworth, NJ.
authors: Wen
authors: W
authors: Liu
authors: Merck & Co, Inc, Kenilworth, NJ.
authors: Tom
authors: T
authors: Reynders
authors: Merck & Co, Inc, Kenilworth, NJ.
authors: Jean Francois
authors: JF
authors: Denef
authors: Merck & Co, Inc, Kenilworth, NJ.
authors: Anna
authors: A
authors: Mitselos
authors: Merck & Co, Inc, Kenilworth, NJ.
authors: Daniel
authors: D
authors: Jonathan
authors: Merck & Co, Inc, Kenilworth, NJ.
authors: David E
authors: DE
authors: Gutstein
authors: Merck & Co, Inc, Kenilworth, NJ.
authors: Kaushik
authors: K
authors: Mitra
authors: Merck & Co, Inc, Kenilworth, NJ.
authors: Shu Yu
authors: SY
authors: Sun
authors: Merck & Co, Inc, Kenilworth, NJ.
authors: Michael Man-Chu
authors: MM
authors: Lo
authors: Merck & Co, Inc, Kenilworth, NJ.
authors: Doris
authors: D
authors: Cully
authors: Merck & Co, Inc, Kenilworth, NJ amjad_ali@merck.com.
authors: Amjad
authors: A
authors: Ali
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D006152:Cyclic GMP / Q000378:metabolism; D004285:Dogs; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D066298:In Vitro Techniques; D007687:Kidney Tubules, Proximal / Q000166:cytology; D008297:Male; D008875:Middle Aged; D020030:Nitric Oxide Donors / Q000494:pharmacology* / Q000627:therapeutic use; D014226:Triazenes / Q000494:pharmacology* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: C000625933:MK-8150; D020030:Nitric Oxide Donors; D014226:Triazenes; D006152:Cyclic GMP
keywords: blood pressure; nitrate; nitrate tolerance; nitric oxide; vasodilation