In spontaneously hypertensive rats, HM17321 reduced urinary albumin-to-creatinine ratio to 45.5% and 24-hour urinary albumin excretion to 42.2% of vehicle-treated levels.
Does HM17321 improve cardiovascular and renal outcomes in spontaneously hypertensive rats?
In a preclinical model of hypertension, the novel UCN2 analog HM17321 reduced blood pressure, improved body composition, and attenuated renal dysfunction and cardiac hypertrophy.
Introduction and Objective: A novel UCN2 analog, HM17321, was developed to enhance CRFR2 selectivity and extend therapeutic benefits beyond improvements in weight loss quality (WLQ) to include the cardiovascular and renal systems. Here, we investigated the effects of HM17321 on renal dysfunction and explored the underlying mechanisms. Methods: Renal and cardiovascular effects of HM17321 were evaluated in SHR. Blood pressure (BP) was continuously monitored by telemetry, and a long-term efficacy study assessed renal and cardiac outcomes, with semaglutide (Sema) as a comparator. Results: In SHR, HM17321 reduced systemic BP and heart rate, with concomitant increases in blood NO levels, suggesting NO-mediated vasodilation and a strong potential to improve cardiovascular (CV) risk. In a 4-month study, HM17321 consistently improved WLQ, as evidenced by marked fat mass reduction (up to -45.5 percentage points vs. SHR) and lean mass gain (up to +9.7 percentage points) with no change in body weight. Notably, HM17321 prevented progressive renal function deterioration observed in vehicle- and Sema-treated SHR. Urinary albumin-to-creatinine ratio and 24-hour urinary albumin excretion were significantly reduced by HM17321 at 300 nmol/kg to 45.5% and 42.2% of vehicle-treated SHR levels, respectively. HM17321 also significantly attenuated cardiac hypertrophy, as evidenced by reduced heart weight. Comprehensive tissue-level analyses of cardiac and renal remodeling are currently underway. Additional mechanistic studies will further delineate the potential direct renal protective effects of HM17321 beyond BP-lowering-mediated benefits. Conclusion: HM17321 exerted integrated cardiovascular and renal protective effects in preclinical models of hypertension and kidney injury. Beyond its favorable impact on WLQ as a next-generation obesity therapy, HM17321 attenuated the progression of renal dysfunction, supporting its potential applicability as a therapeutic strategy for cardiorenal diseases. Disclosure S. Lee: None. E. Kim: None. Y. Kim: None. D. Lee: None. E. Park: Employee; Current; Hanmi Pharm. Co., Ltd. B. Ye: Employee; Current; Hanmi Pharm. Co., Ltd. J. Kim: Employee; Current; Hanmi Pharm. Co., Ltd. J. Kim: None. S. Bae: None. S. Lee: Employee; Current; Hanmi Pharm. Co., Ltd. I. Choi: None.
LEE et al. (Fri,) conducted a other in Hypertension and kidney injury. HM17321 vs. Vehicle and semaglutide was evaluated on Urinary albumin-to-creatinine ratio and 24-hour urinary albumin excretion. In spontaneously hypertensive rats, HM17321 reduced urinary albumin-to-creatinine ratio to 45.5% and 24-hour urinary albumin excretion to 42.2% of vehicle-treated levels.