Preclinical toxicity evaluation of the novel anti-hypertensive compound KSD179019.

Abstract

The Secretin receptor (SCTR) presents a promising path for hypertension management, with KSD179019 as identified as a Positive Allosteric Modulator (PAM) of SCTR, demonstrating anti-hypertensive effects in animal models. Our objective was to comprehensively evaluate the potential toxicity of KSD179019 through in vitro and in vivo investigations. Initial in vitro studies showed minimal toxicity in liver and kidney cells and non-mutagenicity in bacterial assays. A 14-day acute toxicity test indicated an LD50 over 5000 mg/kg body weight, suggesting a safe profile, yet necessitating further in vivo analysis before progressing to human trials. Following OECD protocols, we conducted sub-chronic (90 days) and chronic (180 days) toxicity studies in male and female C57 mice at various dosages. These included comprehensive hematological, biochemical, macroscopic, urinalysis, and histopathological examinations. The sub-chronic study reported minimal toxicity except at the highest doses (700 and 1000 mg/kg), while the chronic study suggested a no-observed-adverse-effect-level (NOAEL) at 250 mg/kg with limitations. QSAR analysis supported the non-mutagenic nature of KSD179019. KSD179019 demonstrated a favorable general toxicity profile at a dose of 250 mg/kg in a 180-day chronic testing study. However, further preclinical investigations, including assessments of in vivo mutagenicity, reproductive and developmental toxicity, and carcinogenicity, are required to comprehensively establish its safety profile.