Discovery of Triazole Derivatives as Prokineticin Receptor 1 (PROKR1) Agonist for Treatment of Sarcopenia

Abstract

Prokineticin receptor 1 (PROKR1) is a G protein-coupled receptor that plays a crucial role in skeletal muscle metabolism through the Gs-cAMP-CREB signaling axis and upregulation of oxidative myofiber gene expression. Based on this mechanism, we designed a series of 1,2,4-triazole derivatives as novel PROKR1 agonists and synthesized using a Kuskov-type reaction followed by a Sawdey rearrangement. In addition, structure-activity relationship (SAR) studies were conducted based on in vitro experimental results. Among the synthesized compounds, 1-(4-(Difluoromethoxy)phenyl)-N'-(naphthalen-2-yl)-5-phenyl-1H-1,2,4-triazole-3-carbohydrazide (12f) was identified as a lead candidate, demonstrating potent PROKR1 agonistic activity, enhanced oxidative myogenic differentiation in vitro, favorable metabolic stability, and pharmacokinetics behavior. In diet-induced obesity (DIO) mice, once-daily administration led to marked reduced body weight while increasing lean mass. DEXA imaging further confirmed a shift toward a more favorable body composition. Moreover, the lead compound enhanced skeletal muscle mass-particularly in the quadriceps-and improved functional performance, including grip strength and ambulatory activity. Safety assessments further indicated no observable cardiotoxicity and low CYP450 inhibition liabilities, supporting its suitability for further preclinical development. Collectively, these findings highlight the lead compound as a promising PROKR1 agonist capable of improving skeletal muscle metabolism and physical function. Its potential therapeutic evaluation in age-related sarcopenia models will further validate its translational applicability.