title: Pharmacokinetics and pharmacodynamics of MK-5046, a bombesin receptor subtype-3 (BRS-3) agonist, in healthy patients.
abstract: MK-5046 is an orally active, potent, selective agonist of the orphan G protein-coupled receptor bombesin receptor subtype-3 (BRS-3) that is under evaluation for treatment of obesity. We report the safety, tolerability, pharmacokinetics, and pharmacodynamics of oral doses of MK-5046 (10-160 mg) in a double-blind, randomized, placebo-controlled study in healthy and obese male volunteers. MK-5046 exposure increased dose proportionally, and MK-5046 was eliminated with an apparent terminal half-life of 1.5 to 3.5 hours. Single doses transiently increased blood pressure. Patients reported adverse events (erections and feeling hot, cold, and/or jittery) that coincided with time of occurrence (T(max)) and increased with increasing dose. No changes were observed in body temperature, heart rate, plasma glucose levels, or feelings of hunger/satiety. The blood pressure and thermal experiences attenuated with a second dose 6 hours after the first. Additionally, the erections suggest a possible, unanticipated, role for BRS-3 in reproductive physiology. Oral administration of MK-5046 achieves plasma concentrations that are projected to activate BRS-3 and therefore should be suitable for exploring its biological role in humans.
authors.affiliation: Clinical Pharmacology, Merck Research Laboratories, Rahway, New Jersey 07065-0900, USA.
authors.forename: Marc L
authors.initials: ML
authors.lastname: Reitman
authors.forename: Victor
authors.initials: V
authors.lastname: Dishy
authors.forename: Allison
authors.initials: A
authors.lastname: Moreau
authors.forename: William S
authors.initials: WS
authors.lastname: Denney
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Liu
authors.forename: Walter K
authors.initials: WK
authors.lastname: Kraft
authors.forename: Alex V
authors.initials: AV
authors.lastname: Mejia
authors.forename: Mark A
authors.initials: MA
authors.lastname: Matson
authors.forename: S Aubrey
authors.initials: SA
authors.lastname: Stoch
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
authors.forename: Eseng
authors.initials: E
authors.lastname: Lai
mesh_terms: D019440:Anti-Obesity Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D001066:Appetite / Q000187:drug effects; D019540:Area Under Curve; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D004311:Double-Blind Method; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D007328:Insulin / Q000097:blood; D008297:Male; D011720:Pyrazoles / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D018004:Receptors, Bombesin / Q000819:agonists*
chemical_list: C556243:1,1,1-trifluoro-2-(4-(1H-pyrazol-1-yl)phenyl)-3-(4-((1-(trifluoromethyl)cyclopropyl)methyl)-1H-imidazol-2-yl)propan-2-ol; D019440:Anti-Obesity Agents; D001786:Blood Glucose; D007093:Imidazoles; D007328:Insulin; D011720:Pyrazoles; D018004:Receptors, Bombesin; C107120:bombesin receptor subtype 3