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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 (Tmax) 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.