Pharmacokinetics and pharmacodynamics of MK-5046, a bombesin receptor subtype-3 (BRS-3) agonist, in healthy patients.

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.